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Molecular Conceptor - Table of Contents
Structural BioinformaticsLast updated on September 2012
A - DRUG DISCOVERY
1. Introduction to Drug Discovery
2. Principles of Rational Drug Design
B - PROTEIN STRUCTURE AND MODELING
1. Structural Bioinformatics (in progress)
2. Protein Structure
3. Molecular Dynamics
C - STRUCTURE-BASED DESIGN
1. Introduction to Protein-Ligand Binding
2. Principles of Structure-Based Design
3. Molecular Docking: Principles and Methods
4. Case Studies in Structure-Based Design
5. Case Studies of Docking in Drug Discovery
6. Analyses of Protein-Ligand Complexes
D - MOLECULAR BASIS OF DRUGS
1. Molecular Geometry
2. Molecular Properties 3. Stereochemistry
4. Molecular Energies
5. Conformational Analysis
6. Molecular Graphics
7. Selected Examples in 3D Analysis
E - GENERAL TOPICS
1. General Introduction to Drugs
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2. Drug Discovery
3. Drug Development
A. DRUG DISCOVERY
A1. INTRODUCTION TO DRUG DISCOVERY
A1.1 From the Origin of Medicines to Today
A1.1.1 Attempts to Cure Diseases in Antiquity
A1.1.2 Medicines Used in Ancient Civilizations
A1.1.3 5th-4th BC Centuries: The Greek Period
A1.1.4 2nd Century: The Roman Period
A1.1.5 13th Century: The Arab School
A1.1.6 13th Century: First Apothecary Shops
A1.1.7 16th Century: Pharmaceutical Science
A1.1.8 16th Century: Maritime Routes to India and America
A1.1.9 18th Century: First Vaccine
A1.1.10 19th Century: Drug Administration
A1.1.11 19th Century: Isolation of Compounds
A1.1.12 19th Century: Relief of Pain in Surgical Operations
A1.1.13 19th Century: New Classes of Drugs
A1.1.14 20th Century: Pioneer Work of Paul Ehrlich
A1.1.15 20th Century: Sulfonamide Antibacterial Dyes
A1.1.16 20th Century: Recognition of Vitamins
A1.1.17 20th Century: The Antibiotic Era
A1.1.18 20th Century: Pfizer Management Decision
A1.1.19 20th Century: Large Scale Production of Penicillin
A1.1.20 20th Century: Antibacterial Agents Isolated from Plants
A1.1.21 20th Century: Discovery of Adrenal Cortex Hormones
A1.1.22 20th Century: NSAIDs
A1.1.23 20th Century: Key Transition Discoveries
A1.1.24 20th Century: Some Drug Discovery Projects
A1.1.25 Example-1 of Project: Factor Xa
A1.1.26 Example-2 of Project: Motilin Antagonists
A1.1.27 Example-3 of Project: COX-2 Inhibitors
A1.1.28 Example-4 of Project: Rotamase Inhibitors
A1.1.29 20th Century: From Apothecaries to Factories
A1.2 Revolutions that Changed Drug Discovery
A1.2.1 Major Achievements
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A1.2.2 Understanding Drug-Receptor Recognition
A1.2.3 Consolidation of Concept of Biological Targets
A1.2.4 Recombinant Technologies and Cloning of Genes
A1.2.5 Deciphering the Sequences of Genomes
A1.2.6 Determination of Proteins 3D Architectures A1.2.7 Automated Methods in Synthetic Chemistry
A1.2.8 HTS Screening
A1.2.9 Automation in Drug Discovery
A1.2.10 In-Silico Modeling becomes Mature
A1.3 In-Silico Technologies
A1.3.1 The Explosion of In-Silico Technologies
A1.3.2 Encoding Molecules: 2D and 3D Databases
A1.3.3 Development of Molecule Encoding
A1.3.4 3D Searching is not Trivial A1.3.5 Encoding Molecular Properties
A1.3.6 Development of Models for Data Analysis
A1.3.7 Molecular Modeling
A1.3.8 Development of Computer Graphics
A1.3.9 Development of Models for Data Visualization
A1.3.10 In-Silico Molecular Mechanics
A1.3.11 In-Silico Molecular Dynamics
A1.3.12 In-Silico Docking
A1.3.13 In-Silico Virtual Screening
A1.3.14 3D Searching and Bioisosterism A1.3.15 Pharmacophore Elucidation and Mapping
A1.3.16 Structure-Activity Relationships - SAR
A1.3.17 Chemometrics
A1.3.18 Development of QSAR
A1.3.19 3D-QSAR
A1.3.20 In-Silico Library Design
A1.3.21 In-Silico Homology Modeling
A1.3.22 In-Silico Free Energy Simulations
A1.3.23 Cheminformatics
A1.3.24 Structural Bioinformatics A1.3.25 Reaction Searching
A1.3.26 Computer-Assisted Structure Elucidation
A1.3.27 In-Silico Prediction of ADME/Tox Properties
A1.3.28 Quantum Chemical Calculations
A1.4 The Drug Discovery Process
A1.4.1 Outline of Drug Discovery
A1.4.2 Starting Idea in a Project
A1.4.3 Importance of Assay Validation
A1.4.4 The Drug Discovery Process
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A1.4.5 Starting Molecule in a Project
A1.4.6 Optimization of the Lead
A1.4.7 Potency and Selectivity
A1.4.8 Beyond Potency and Selectivity in Lead Optimization
A1.4.9 Drugability A1.4.10 Resistance
A1.4.11 Pharmacodynamics
A1.4.12 Drug Delivery
A1.4.13 Metabolism
A1.4.14 Bioavailability
A1.4.15 Toxicity
A1.4.16 Patentability
A1.4.17 Protection of Drug Discovery Achievements
A1.4.18 Lifetime and Effective Lifetime of a Patent
A1.4.19 Assessing Patentability: The Viagra-Levitra Example
A1.4.20 Drug Discovery before and after 1980
A1.4.21 Intelligent Management Strategy
A1.5 Rational Drug Design Strategy
A1.5.1 Two Major Approaches
A1.5.2 Underlying Principles
A1.5.3 Contribution of Molecular Modeling
A1.5.4 The Molecular Similarity Principle
A1.5.5 The Molecular Complementarity
A1.5.6 The Concept of 2D and 3D Pharmacophores A1.5.7 Structure-Based Drug Discovery: The Aliskiren Example
A1.5.8 Therapeutic Risk in a Project
A1.6 The Major Players in Drug Research
A1.6.1 Role of Each Scientist
A1.6.2 Organic Chemist
A1.6.3 Prepare new Molecules
A1.6.4 Analyze SAR Data
A1.6.5 Order new Molecules and Libraries
A1.6.6 Design of a Library of Molecules
A1.6.7 Scale Up a Chemical Synthesis
A1.6.8 Biologist
A1.6.9 Develop Biological Assays
A1.6.10 Develop in-vivo Models for Testing new Molecules
A1.6.11 Test New Molecules
A1.6.12 Compare Results Obtained by Other Groups
A1.6.13 Develop Models for Early Assessment of Toxicity
A1.6.14 Implement Platform for High Throughput Screening
A1.6.15 Molecular Modeler
A1.6.16 Provide Structural Models of Good Quality
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A1.6.17 Analyze and Suggest Candidate Molecules
A1.6.18 Assess Molecules Submitted the Team
A1.6.19 Explore Ways for 3D Alignment of Molecules
A1.6.20 Biotechnologist
A1.6.21 Cloning DNA Sequences A1.6.22 Isolation of Enzyme
A1.6.23 Identify Disease-Relevant Target
A1.6.24 Validate a New Assay
A1.6.25 Computational Chemist
A1.6.26 Search for a Predictive 3D-QSAR Model
A1.6.27 Launch High Throughput Docking Simulations
A1.6.28 Estimate the Binding Energies of New Molecules
A1.6.29 Assess the Quality of QSAR Models
A1.6.30 Structural Bioinformatician
A1.6.31 Encoding and Visualizing Biomolecules
A1.6.32 Understand Protein Flexibility
A1.6.33 Create 3D Models of new Proteins
A1.6.34 Decode the Function of a Protein from its 3D Structure
A1.6.35 Reveal Key Residues in a Protein
A1.6.36 Cheminformatician
A1.6.37 Calculate Molecular Properties
A1.6.38 Find Similar Molecules
A1.6.39 Analyze HTS Results
A1.6.40 Contribute to Virtual Screening and Library Design
A1.6.41 Update and Maintain Databases
A1.6.42 Biophysicist
A1.6.43 X-Ray Crystallographer
A1.6.44 Prepare Crystals of a Protein or a Complex
A1.6.45 Diffraction Pattern and Density Map
A1.6.46 Fit the Electron Density Map
A1.6.47 Refine the 3D Atomic Model
A1.6.48 NMR Spectroscopist
A1.7 Chemistry in Drug Discovery
A1.7.1 Chemistry in Drug Discovery A1.7.2 Synthesis of Complicated Molecules
A1.7.3 Three Methods in Synthetic Chemistry
A1.7.4 Classical Drug Discovery
A1.7.5 Parallel Drug Discovery
A1.7.6 Combinatorial Drug Discovery
A1.7.7 Chemistry in Lead Discovery
A1.7.8 Protein Kinase Example
A1.7.9 Lead Optimization
A1.7.10 Example: Optimization of the Gleevec Series
A1.7.11 Chemistry in Drug Development
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A1.8 The Present and Future Face of Drug Discovery
A1.8.1 Outsourcing: an Important Cultural Shift
A1.8.2 Why Outsourcing Develops so Well?
A1.8.3 Management Response to Challenging Situations A1.8.4 Management Challenges
A1.8.5 Mergers and Mega-Mergers
A1.8.6 Drug Discovery and Mergers
A1.8.7 Massive Cut of Jobs Following Mergers
A1.8.8 Headcount are not always Reduced
A1.8.9 Creation and Development of Startup Companies
A1.8.10 Startup Example-1: Amgen
A1.8.11 Startup Example-2: Actelion
A1.8.12 Startup Example-3: Speedel
A1.8.13 Increasing Importance of Generics
A1.8.14 Economical Implications of Generics
A1.8.15 Emergence of New Industrial Players
A1.8.16 Pharmaceutical Industry in India and China
A1.8.17 Personalized Medicines
A1.8.18 Pharmacogenomics Example
A1.8.19 Stem Cell Therapy
A1.8.20 Some Facts and Figures
A1.8.21 The Cost of Developing a New Drug
A1.8.22 The R&D Process
A1.8.23 Innovation of Drug Discovery (1997-2007)
A1.8.24 Improvements in Life Expectancy
A1.8.25 Drug Discovery in the Industry
A1.8.26 Success of Drug Discovery (in 2008)
A1.8.27 60 Years of Drug Discovery Achievements
A1.8.28 Concluding Remarks
A2. PRINCIPLES OF RATIONAL DRUG DESIGN
A2.1 Rational Drug Design
A2.1.1 Drug Design Basis: Molecular Recognition
A2.1.2 Lock-and-Key Model
A2.1.3 Induced-Fit Model
A2.1.4 Rational Drug Design
A2.1.5 Rational Drug Design Process
A2.1.6 Receptor-Based Drug Design
A2.1.7 Pharmacophore-Based Drug Design
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A2.2 Pharmacophore-Based Design
A2.2.1 Pharmacophore-Based Drug Design Approach
A2.2.2 Similarity Concepts and Molecular Mimicry
A2.2.3 Examples of Molecular Mimicry A2.2.4 ATP
A2.2.5 Dopamine
A2.2.6 Histamine
A2.2.7 Estradiol
A2.2.8 Peptidomimetics
A2.2.9 Strengths of Pharmacophore-Based Drug Design
A2.3 Receptor-Based Design
A2.3.1 Design by Direct Interaction with Receptor Sites
A2.3.2 Exploiting the Receptor Recognition Concepts A2.3.3 Initial Data in Receptor-Based Drug Design
A2.3.4 Strengths of Receptor Based Drug Design
A2.4 Integration in a Global Perspective
A2.4.1 Typical Projects
A2.4.2 Exploit the Two Methods, Independently
A2.4.3 Synergy Between the Two Approaches
A2.4.4 Example of Synergy Between the Two Approaches
A2.4.5 Good Binding Models, the Synergy Condition
A2.4.6 Ideal Situation
A2.4.7 Example 1
A2.4.8 Example 2
A2.4.9 Integration in a Global Perspective
A2.4.10 Pharmacophore-Based Drug Design
A2.4.11 Receptor-Based Drug Design
A2.4.12 Integrated Global Approach
A2.5 Challenge of the Genomics Era
A2.5.1 The Genomic Era A2.5.2 A New Challenge in Drug Design
A2.6 Typical Projects
A2.6.1 Typical Pharmacophore-Based Project
A2.6.2 Design Based on 3D Mimicry
A2.6.3 Typical Receptor-Based Project
A2.6.4 Design Based in Making Favorable 3D Interactions
A2.6.5 Typical Genomic Project
A2.7 Perspectives
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A2.7.1 Drug Discovery of the 1970's
A2.7.2 Drug Discovery of the 1980's
A2.7.3 Drug Discovery of the 1990's
A2.7.4 The Present Situation
A2.7.5 Initial Skepticism Towards Rational Drug Design A2.7.6 Success Stories in Rational Drug Design
A2.7.7 Future Perspectives
A2.8 CHAPTER QUIZZES (Available only in Academic License)
B. PROTEIN STRUCTURE AND MODELING
B1. STRUCTURAL BIOINFORMATICS
B1.1 Introduction to Structural Bioinformatics
B1.1.1 Challenges in the Post Genomic Era
B1.1.2 The Informational Chaos
B1.1.3 Integration through Computational Science
B1.1.4 Structural Bioinformatics
B1.1.5 Grouping Fields into One Discipline
B1.1.6 3D Basis of Structural Bioinformatics
B1.1.7 The Structural Genomics Effort
B1.1.8 The Protein Structure Initiative
B1.1.9 Strategy of the Protein Structure Initiative
B1.1.10 The Structural Genomics Consortium
B1.1.11 Global Planning of Structural Genomics
B1.1.12 The Impact of Structural Genomics
B1.1.13 The Relationship between Structure and Function
B1.1.14 Example of a Structure-Function Relationship
B1.1.15 Learning from Evolution
B1.1.16 Learning from Structural Folds
B1.1.17 Learning from Molecular Shape
B1.1.18 Example of Knowledge Derived from 3D Structure
B1.1.19 Is Structure Sufficient to Predict Function?
B1.1.20 Exploiting Knowledge to Design New Drugs
B1.1.21 Bridge between Genomics and Drug Discovery
B1.1.22 Tools Developed by Structural Bioinformatics
B1.2 Architecture of Biomolecules
B1.2.1 Biomolecules in the Cell
B1.2.2 DNA/RNA Structure
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B1.2.3 DNA is the Genetic Material
B1.2.4 DNA Variability
B1.2.5 Importance of the DNA 3D Structure
B1.2.6 The Building Blocks
B1.2.7 Base B1.2.8 Sugar
B1.2.9 Phosphate
B1.2.10 Putting the Building Blocks Together
B1.2.11 Nomenclature of Nucleotides and Nucleosides
B1.2.12 Nucleotides of Nucleic Acids
B1.2.13 The Double Helix Structure
B1.2.14 DNA Helices are Antiparallel
B1.2.15 Hydrogen Bonding Pattern
B1.2.16 Aromatic Base Stacking
B1.2.17 Major and Minor Grooves
B1.2.18 DNA forms
B1.2.19 G-Quadruplex Conformation
B1.2.20 DNA versus RNA
B1.2.21 3D Folds of RNA
B1.2.22 Protein Structure
B1.2.23 Proteins are Fundamental to Life
B1.2.24 Structural Diversity of Proteins
B1.2.25 Importance of Protein 3D Structures
B1.2.26 Chemical Nature of Proteins
B1.2.27 Challenges in Understanding Protein Structure
B1.2.28 Protein Structure Complexity
B1.2.29 The Four Levels of Protein Architecture
B1.2.30 Primary Structure
B1.2.31 Secondary Structure
B1.2.32 Tertiary Structure
B1.2.33 Quaternary Structure
B1.3 Biomolecular Properties
B1.3.1 Protein Flexibility and Motion
B1.3.2 Importance of Dynamic Motions in Biological Processes B1.3.3 Example of Function: ATP Synthase
B1.3.4 Example of Function: DNA Biosynthesis
B1.3.5 Example of Function: Molecular Switch
B1.3.6 Example of Induced-Fit: RNA-Protein Recognition
B1.3.7 Example of Induced-Fit: Ubiquitous Proteins
B1.3.8 Types of Molecular Motions
B1.3.9 Time Scale of Protein Motion
B1.3.10 Methods to Study Protein Motions
B1.3.11 Experimental Techniques to Study Protein Motions
B1.3.12 Simulation Methods to Study Protein Motions B1.3.13 Normal Mode Analyses (NMA)
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B1.3.14 Molecular Dynamics vs Normal Mode Analyses
B1.3.15 Database of Macromolecular Movements
B1.4 Assembly of Biomolecules
B1.4.1 Biological Molecule Association
B1.4.2 Molecular Recognition
B1.4.3 The Recognition Process
B1.4.4 Complementary Features Upon Binding
B1.4.5 Role of Native Protein Configuration
B1.4.6 Tolerance Upon Binding
B1.4.7 The "Induced-Fit" Theory
B1.4.8 Example of Enzyme Adaptation to Inhibitor Binding
B1.4.9 Example of Ligand Adaptation upon Binding
B1.4.10 Maximizing Surface Contacts
B1.4.11 Motions Associated to Induced-Fit B1.4.12 Experimental Evidence of the Induced-Fit Model
B1.4.13 Large Rearrangements
B1.4.14 Role of Large Rearrangements
B1.4.15 The Domino Effect
B1.4.16 Proteins Described as Ensemble of Conformations
B1.4.17 Energy Landscape of a Protein
B1.4.18 Conformational Selection Operated by a Ligand
B1.4.19 Energetic Induction Upon Binding
B1.4.20 Forces Involved in Molecular Recognition
B1.4.21 Van der Waals Forces B1.4.22 Electrostatic Interactions
B1.4.23 Hydrogen Bonds
B1.4.24 Solvent Effect
B1.4.25 The Role of the Solvent
B1.4.26 The Hydrophobic Effect
B1.4.27 The Entropic Effects
B1.4.28 Enthalpy-Entropy Compensation
B1.4.29 Assessing Binding Interactions
B1.4.30 Free Energy of Binding
B1.4.31 Importance of Free Energy of Binding B1.4.32 Experimental Measures of Binding Affinities
B1.4.33 Titration Curve to Measure Kd
B1.4.34 Scatchard-Rosenthal Plots
B1.4.35 Conversion of Kd into Energies
B1.4.36 Theoretical Prediction of Binding Energies
B1.4.37 Solving the Schrodinger Equation
B1.4.38 Molecular Mechanics
B1.4.39 Force-Field
B1.4.40 Example of Force-Fields
B1.4.41 Other Methods B1.4.42 Incorporation of the Solvent
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B1.5 Obtaining Macromolecular 3D-Structures
B1.5.1 Experimental Methods
B1.5.2 X-ray Crystallography
B1.5.3 Protein Production and Purification B1.5.4 Growing of Single Crystal
B1.5.5 The Single Crystal
B1.5.6 Collecting the Diffraction Data
B1.5.7 Recovering the Phase Angle
B1.5.8 Structure Determination and Refinement
B1.5.9 Atomic Coordinates
B1.5.10 The Advantages of X-ray Crystallography
B1.5.11 The Limitations of X-ray Crystallography
B1.5.12 NMR Spectroscopy
B1.5.13 NMR Concepts
B1.5.14 Spin-Spin Coupling
B1.5.15 Data Collection
B1.5.16 Structure Determination
B1.5.17 Analysis
B1.5.18 The Advantages of NMR
B1.5.19 The Limitations of NMR
B1.5.20 Electron Microscopy
B1.5.21 Basic Concept
B1.5.22 The Advantages of Electron Microscopy
B1.5.23 The Limitations of Electron Microscopy
B2. PROTEIN STRUCTURE
B2.1 Structural and Functional Diversity of Proteins
B2.1.1 Proteins are Fundamental to Life
B2.1.2 Great Diversity of Protein Biological Functions
B2.1.3 Chemical Nature of Proteins
B2.1.4 Structural Diversity of Proteins
B2.2 Link between Protein Sequence, Folding and Function
B2.2.1 Importance of Protein 3D Structures
B2.2.2 Protein Folding
B2.2.3 Anfinsen's Dogma
B2.2.4 Anfinsen's Dogma and Levinthal's Paradox
B2.2.5 The Pathway Theory and Energy Funnels
B2.2.6 Mechanisms of Protein Folding
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B2.2.7 The Protein Misfolding Problem
B2.2.8 Challenge in Understanding Protein Structure
B2.3 Amino Acids: Building Blocks of Proteins
B2.3.1 Amino acids: Building Blocks of Proteins
B2.3.2 α-Amino Acids
B2.3.3 α-Amino Acid Stereoisomers
B2.3.4 Diversity of the Properties of Amino Acids
B2.3.5 Amino Acids Properties
B2.3.6 Classification of Amino Acids Properties
B2.3.7 Non-Standard Amino Acids
B2.4 From Amino Acids to Proteins
B2.4.1 Amino Acids are Linked by Peptide Bonds
B2.4.2 Peptide Biosynthesis
B2.4.3 Polymer Amino-Acids
B2.4.4 Length of Proteins
B2.4.5 More than One Polypeptide Chain
B2.4.6 Conjugated Proteins
B2.4.7 Examples of Conjugated Proteins
B2.4.8 Cross-Linked Polypeptide Chains
B2.5 Geometry of Proteins and Peptides
B2.5.1 Peptide Bonds are Planar B2.5.2 Why the Peptide Bond is Planar?
B2.5.3 Cis and Trans Isomers of the Peptide Bond
B2.5.4 Trans Isomer Favored
B2.5.5 Isomers of Proline
B2.5.6 Peptide Torsion Angles
B2.5.7 Conformational Freedom
B2.5.8 Conformational Complexity of Polypeptide Chains
B2.5.9 Not All φ / ψ Torsion Angles are Possible
B2.5.10 The Ramachandran Plot
B2.5.11 φ and ψ Distribution B2.5.12 Interactive Ramachandran Plot
B2.5.13 Torsion Angles Observed in Proteins
B2.5.14 Glycine Residue Torsion Angles
B2.5.15 Side Chain Conformations
B2.5.16 Side Chain Atomic and 3D Nomenclature
B2.5.17 Side Chain Conformations
B2.5.18 Non-Rotameric Side Chain Conformations
B2.6 Protein Structure Overview
B2.6.1 Protein Structure Complexity
B2.6.2 The Four Levels of Protein Architecture
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B2.6.3 Primary Structure
B2.6.4 Secondary Structure
B2.6.5 Tertiary Structure
B2.6.6 Quaternary Structure
B2.6.7 Forces Involved in Protein Stability B2.6.8 Proteins are not Static
B2.6.9 Representing Protein Structures
B2.6.10 Wireframe Representation
B2.6.11 Ball and Stick Representation
B2.6.12 Cα Trace Representation
B2.6.13 Ribbon Representation
B2.6.14 Cartoon Representation
B2.6.15 Space Filling - CPK Representation
B2.6.16 Surface Representation
B2.7 Primary Structure
B2.7.1 Primary Structure
B2.7.2 Unique Primary Structure for Each Protein
B2.7.3 Primary Sequence and Protein Properties
B2.8 Secondary Structure
B2.8.1 Secondary Structure
B2.8.2 Periodic and Non Periodic Secondary Structure Elements
B2.8.3 Hydrogen Bonds in Secondary Structure Elements
B2.8.4 The α-Helix
B2.8.5 Packing of the α-Helix
B2.8.6 φ and ψ Torsion Angles of the α-Helix
B2.8.7 Two Enantiomeric α-Helices
B2.8.8 Geometry Described with Pitch and Rise
B2.8.9 Helix Macro-Dipole
B2.8.10 Amphipathic Character of the α Helix
B2.8.11 3(10)-Helix and π-Helix
B2.8.12 Helices Geometrical Parameters
B2.8.13 Occurrence of Helices in Proteins
B2.8.14 The β-Sheet
B2.8.15 The β-Strand Unit
B2.8.16 φ and ψ Torsion Angles in β-Sheets
B2.8.17 Stability of the β-Sheet
B2.8.18 Parallel and Anti-Parallel β-Sheets
B2.8.19 Occurrence of β-Sheets in Proteins
B2.8.20 Twist of the β-sheet
B2.8.21 Turns
B2.8.22 β-Turns
B2.8.23 φ and ψ Torsion Angles of β Turns
B2.8.24 Non-Regular Coil and Loops
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B2.8.25 Coil
B2.8.26 Loops
B2.9 Super-Secondary Structure (Motifs)
B2.9.1 Super-Secondary Structures and Motifs
B2.9.2 Classification of Super-Secondary Structures
B2.9.3 All β super-secondary structures
B2.9.4 β-Hairpin
B2.9.5 β-Meander
B2.9.6 Greek-Key
B2.9.7 All α Super-Secondary Structures
B2.9.8 αα-Hairpin
B2.9.9 αα-Corners
B2.9.10 EF Hand
B2.9.11 Helix-Turn-Helix B2.9.12 Four-Helix Bundle
B2.9.13 Mixed α & β Super-Secondary Structures
B2.9.14 β-α-β Motif
B2.9.15 Rossmann Fold
B2.10 Tertiary Structure
B2.10.1 Tertiary Structure
B2.10.2 Domains in the Tertiary Structure
B2.10.3 Domains and Sequence
B2.10.4 Domains and Function
B2.10.5 New Look on Proteins Levels of Architecture
B2.10.6 Blurred Boundaries
B2.10.7 Tertiary Structure Patterns: Folds
B2.10.8 Fold Diversity
B2.10.9 Protein Folds and Function
B2.10.10 Classification of Protein Folds
B2.10.11 Mainly α Folds
B2.10.12 Mainly β Folds
B2.10.13 Mixed α-β Folds
B2.10.14 Databases of Folds
B2.11 Quaternary Structure
B2.11.1 Quaternary Structure
B2.11.2 Dimers, Trimers, Tetramers etc...
B2.11.3 Homo-Oligomers: Identical Polypeptide Chains
B2.11.4 Hetero-Oligomers: Different Polypeptide Chains
B2.12 Structural Classification of Proteins
B2.12.1 Structural Classification of Proteins
B2.12.2 Globular Proteins
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B2.12.3 Hydrophilic Surface and Hydrophobic Core
B2.12.4 Hydrophobic Effect
B2.12.5 Hydration Layer
B2.12.6 Membrane Proteins
B2.12.7 The Lipid Bilayer B2.12.8 Membrane Model
B2.12.9 Membrane Proteins Types
B2.12.10 Transmembrane Protein Surface
B2.12.11 Transmembrane Protein Folds
B2.12.12 Fibrous Proteins
B2.12.13 Collagen
B2.12.14 α-Keratin
B2.12.15 Silk Fibroin
B2.13 Perspectives
B2.13.1 The History
B2.13.2 The Pharmaceutical Connection
B2.13.3 A Fascinating Field
B2.14 CHAPTER QUIZZES (Available only in Academic License)
B3. MOLECULAR DYNAMICS
B3.1 Introduction
B3.1.1 What is Molecular Dynamics?
B3.1.2 Ergodicity Assumption
B3.1.3 Historical Note
B3.1.4 Four Types of Applications of MD Simulation
B3.1.5 Macroscopic Behavior
B3.1.6 MD Between Experiment and Theory
B3.1.7 Refinement and Validation of MD B3.1.8 Access to Unavailable Data
B3.1.9 MD Applied to Living Systems
B3.1.10 Example 1: Relation between Structure and Function
B3.1.11 Example 2: Relation between Structure and Function
B3.1.12 Example 3: Relation between Structure and Function
B3.1.13 Proteins are not Static
B3.1.14 Thermal Fluctuations
B3.1.15 Conformational Changes
B3.1.16 MD as a Way to Study Molecular Motions
B3.1.17 Mimicking the Way a Molecule Moves B3.1.18 Average Properties Derived from MD Trajectories
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B3.1.19 Calculating Molecular Properties of a System
B3.1.20 Studying Thermodynamic Properties
B3.1.21 Studying Kinetic Properties
B3.1.22 Studying Conformational Changes
B3.2 Energy Calculations
B3.2.1 Calculation of Forces & Energies
B3.2.2 Two Families of MD Methods
B3.2.3 The Quantum Mechanics Approach
B3.2.4 Quantum Methods are Computationally Expensive
B3.2.5 The Classical Mechanics Approach
B3.2.6 Classical vs. Quantum Methods
B3.2.7 Classical MD Simulates the Dynamics of the Nuclei
B3.2.8 The Born-Oppenheimer Approximation
B3.2.9 Force Field for Classical MD B3.2.10 General Force Field Equation
B3.2.11 Stretching Term
B3.2.12 Bending Term
B3.2.13 Torsional Term
B3.2.14 Van der Waals Term
B3.2.15 Electrostatic Term
B3.2.16 A Couple of Practical Remarks
B3.2.17 The Link between Forces and Potential Energies
B3.3 MD Algorithm
B3.3.1 Newton's Equation of Motion
B3.3.2 Prediction of Next Position
B3.3.3 Integration Step
B3.3.4 Molecular Dynamics Algorithm
B3.3.5 Trajectories: List of Positions and Velocities
B3.3.6 Atomic Positions at Time (t+∆t)
B3.3.7 Solving Newton's Equations
B3.3.8 Numerical Integration with the Verlet Formula
B3.3.9 Summary of the MD Algorithm
B3.4 Fundamental Issues
B3.4.1 Time Step
B3.4.2 Choice of Time Step
B3.4.3 Time-Scale of Molecular Motions
B3.4.4 Method for Increasing the Time Step: Constrained MD
B3.4.5 Periodic Boundary Condition
B3.4.6 Importance of Long Range Forces
B3.4.7 The Distance Cutoff Concept
B3.4.8 Problems with Cutoffs B3.4.9 Switching Functions
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B3.4.10 Choice of the Cutoff
B3.4.11 Strategies to Incorporate the Solvent
B3.4.12 Implicit Solvent Model
B3.4.13 Explicit Solvent Molecules
B3.4.14 The Ewald Summation Method
B3.5 MD Protocols
B3.5.1 Typical Steps for MD Simulation
B3.5.2 Define and Prepare the Molecular System
B3.5.3 Preparing the Coordinates
B3.5.4 Manual Assembly of a Complex Molecular System
B3.5.5 Solvating the System
B3.5.6 Addition of Counterions
B3.5.7 Choose the MD Package & Force-Field
B3.5.8 Extending the Parameterization of the Force Field B3.5.9 Configuration Parameters of the MD Simulation
B3.5.10 Time-step
B3.5.11 Length of the Simulation
B3.5.12 Distance Cutoffs
B3.5.13 Reassigning the List of Non-Bonded Atom Pairs
B3.5.14 Initial Velocities
B3.5.15 SHAKE Parameters
B3.5.16 Preliminary Treatments: Minimization & Equilibration
B3.5.17 Minimization of Initial Coordinates
B3.5.18 Thermal Equilibration of the System B3.5.19 Maxwell-Boltzmann Equation
B3.5.20 Molecular Dynamics Run
B3.5.21 Conservation of the Total Energy
B3.5.22 Test Energy Fluctuation
B3.5.23 Possible Crash of the Program
B3.6 Analysis of the Results of the MD Simulation
B3.6.1 Analysis of the Results
B3.6.2 Thermodynamic Properties
B3.6.3 Kinetic Properties
B3.6.4 Visualization of Time Dependent Properties
B3.6.5 Deriving Average Properties from the Trajectory
B3.6.6 Average Energies
B3.6.7 Specific Heat
B3.6.8 Radius of Gyration
B3.6.9 Local Motions
B3.6.10 Interesting Motions
B3.6.11 Movies
B3.7 Examples of MD Applications
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B3.7.1 First µs MD Simulation of Protein Folding
B3.7.2 Protein-Folding Dynamics using Folding@Home
B3.7.3 MD of the Complete Satellite Tobacco Mosaic Virus
B3.7.4 How Does RNA Moves Along DNA?
B3.8 Using MD for Conformational Sampling
B3.8.1 The Sampling Approach in Optimization Problems
B3.8.2 MD as a Tool for Sampling the Space
B3.8.3 Sampling to Find the Global Minimum
B3.8.4 Conformational Analysis of a Small Molecule
B3.8.5 Conformational Analysis of Biomolecules
B3.8.6 Loop Conformation in Proteins
B3.8.7 How Do Ligands and Receptors Bind Together?
B3.8.8 Protein Folding Problem
B3.8.9 Systematic and Random Sampling B3.8.10 Alternative Methods for Sampling
B3.8.11 Monte Carlo Random Search
B3.8.12 Monte Carlo Algorithm
B3.8.13 Metropolis Monte Carlo Approach
B3.8.14 Simulated Annealing
B3.8.15 Diffusion Equation Methods
B3.8.16 Replica Exchange MD Method
B3.9 MD for the Calculation of Binding Energies
B3.9.1 In Silico Drug Design
B3.9.2 FEP Approach for Calculating Binding Energies
B3.9.3 FEP Thermodynamic Cycle
B3.9.4 Exploiting the Thermodynamic Cycle
B3.9.5 FEP: Computational Alchemy
B3.9.6 Limitation of FEP Method
B3.9.7 FEP Study: Example 1
B3.9.8 FEP Study: Example 2
B3.10 MD Packages
B3.10.1 Examples of Popular MD Packages
B3.10.2 NAMD
B3.10.3 VMD
B3.10.4 TINKER
B3.10.5 AMBER
B3.10.6 CHARMM
B3.10.7 GROMACS
B3.10.8 MOIL
B3.10.9 GROMOS
B3.11 Limitations and Perspectives
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B3.11.1 Limitations of MD
B3.11.2 Error Introduced by Empirical Potentials?
B3.11.3 Trade Off Between Efficiency and Accuracy
B3.11.4 Supramolecular Systems
B3.11.5 Long Range Forces as a Computational Bottleneck B3.11.6 Time and Size Limitations
B3.11.7 Alternative Techniques for Long Time Dynamics
B3.11.8 From Impossible to Feasible
B3.11.9 Classical MD is not for Bond Breaking Mechanisms
B3.11.10 Present and Future
B3.12 CHAPTER QUIZZES (Available only in Academic License)
C. STRUCTURE-BASED DESIGN
C1. INTRODUCTION TO PROTEIN-LIGAND BINDING
C1.1 Introduction
C1.1.1 Receptor-Based Drug Design
C1.1.2 Macromolecular Targets
C1.1.3 Mechanism of Action of Drugs
C1.1.4 Drug Targets
C1.1.5 Contribution of Recombinant Technologies
C1.1.6 Operational Strategy: Docking
C1.2 Analytical Process
C1.2.1 The Analytical Process
C1.2.2 Data Collection: X-Ray Crystallography
C1.2.3 Data Collection: NMR Spectroscopy
C1.2.4 Data Collection: Homology Models
C1.2.5 Analysis
C1.2.6 Design Phase
C1.3 Principles of Analysis
C1.3.1 Analysis of the Morphology of the Active Site
C1.3.2 Morphology of the Active Site of a Protein Kinase
C1.3.3 Complexes with Ligands
C1.3.4 Forces That Contribute to the Binding
C1.3.5 The Molecular Recognition Process
C1.3.6 Electrostatic C1.3.7 Hydrogen Bonding
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C1.3.8 Hydrophobic
C1.3.9 Hydrophobic Interactions
C1.3.10 Consider Hydrophobic Interactions
C1.3.11 Elementary Hydrophobic Interactions
C1.3.12 Example of Hydrophobic Binding C1.3.13 Strengthening Hydrophobic Interactions
C1.3.14 Hydrogen Bond Features
C1.3.15 Proteins Capabilities in Hydrogen Bonding
C1.3.16 Consider Hydrogen Bond Formations
C1.3.17 Elementary Hydrogen Bond Interactions
C1.3.18 Example of the Hydrogen Bond Binding
C1.3.19 Electrostatic Interactions
C1.3.20 Elementary Electrostatic Interactions
C1.3.21 Strength of Electrostatic Interactions
C1.3.22 Example of Electrostatic Interactions
C1.3.23 Increase of Potency by the Formation of a Salt Bridge
C1.3.24 OH Analog Much Less Potent
C1.4 Example of Tight Interactions
C1.4.1 An Example of a Tight Ligand-Receptor Interaction
C1.4.2 The X-ray Structure of the Biotin/Streptavidin
C1.4.3 The Binding Mode of Biotin with Streptavidin (1/4)
C1.4.4 The Binding Mode of Biotin with Streptavidin (2/4)
C1.4.5 The Binding Mode of Biotin with Streptavidin (3/4)
C1.4.6 The Binding Mode of Biotin with Streptavidin (4/4)
C1.5 Receptor & Ligand Flexibility
C1.5.1 Flexibility of the Receptor
C1.5.2 Flexibility of The Ligand
C1.5.3 Entropic Effects
C1.6 Role of the Solvent
C1.6.1 Solvation and Desolvation
C1.6.2 The Role of the Solvent C1.6.3 Relay with Water Molecules
C1.6.4 Relay with Several Water Molecules
C1.6.5 Relay with Water Molecule Having Four H-Bonds
C1.7 Prediction of Binding Modes
C1.7.1 Binding Modes Predicted by Analogy
C1.7.2 Inversion of Binding Modes
C1.7.3 Inverted Binding Mode of Olomoucine
C1.7.4 X-Ray Structure of ATP Bound to a Protein Kinase
C1.7.5 Intuitive 2D Alignment for Olomoucine
C1.7.6 Experimental Binding Mode of Olomoucine
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C1.7.7 Origin of the Inverted Binding Mode of Olomoucine
C1.7.8 Inverted Binding Mode of Methotrexate
C1.7.9 Intuitive 2D Alignment for Methotrexate
C1.7.10 Experimental Binding Mode of Methotrexate
C1.7.11 Origin of the Inverted Binding Mode of Methotrexate C1.7.12 Binding Mode Predicted from SAR
C1.8 Methods for Analyzing Binding
C1.8.1 Analyzing Ligand-Receptor Binding
C1.8.2 Ligand-Binding Predictions
C1.8.3 Visual Analyses
C1.8.4 Docking Analyses
C1.8.5 Manual Docking with Computer Graphics
C1.8.6 Automated Methods for Docking
C1.8.7 Calculation of Binding Energies C1.8.8 Free Energy Perturbation Techniques
C1.8.9 Energies from Force Field Calculations
C1.8.10 Correlation with Biological Activities
C1.8.11 Energies from Scoring Functions
C1.8.12 Limitations of Scoring Functions
C1.8.13 Calculating Desolvation Energies
C1.9 Conclusion
C1.9.1 Conclusion
C1.10 CHAPTER QUIZZES (Available only in Academic License)
C2. PRINCIPLES OF STRUCTURE-BASED DESIGN
C2.1 Introduction
C2.1.1 Design of Drug Candidates: An Iterative Process
C2.1.2 Steps in Structure-Based Drug Design
C2.1.3 Small Changes Can Produce Huge Effects
C2.1.4 p38 Wild
C2.1.5 p38 Mutant
C2.1.6 ERK-2 Wild
C2.1.7 ERK-2 Mutant
C2.1.8 Increasing Biological Activity
C2.1.9 Beginning the Design Phase
C2.1.10 A Simple Example of Design
C2.1.11 Extension of the Molecule to Form another H-Bond
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C2.1.12 Checking the Validity of the Design
C2.1.13 Definition of Docking
C2.1.14 Docking Treatments
C2.2 Eight Golden Rules
C2.2.1 Eight Golden Rules in Receptor-Based Ligand Design
C2.2.2 Rule 1: Coordinate to Key Anchoring Sites
C2.2.3 Desolvation Upon Binding
C2.2.4 Rule 2: Exploit Hydrophobic Interactions
C2.2.5 Many Small Contributions
C2.2.6 Rule 3: Exploit Hydrogen Bonding Capabilities
C2.2.7 Hydrogen Bonds with Backbone Atoms
C2.2.8 Geometry of a Hydrogen Bond and Solvation Issues
C2.2.9 Hydrogen Bonds with Residue Atoms
C2.2.10 Rule 4: Exploit Electrostatic Interactions C2.2.11 Rule 5: Favor Bioactive Form & Avoid Energy Strain
C2.2.12 Advantage and Limitation of a Rigid Ligands
C2.2.13 Rule 6: Optimize VDW Contacts and Avoid Bumps
C2.2.14 The Frontier between an Excellent Fit and a Bump
C2.2.15 Rule 7: Structural Water Molecules and Solvation
C2.2.16 Desolvation Energies
C2.2.17 Leave Some Room to Solvate Charged Centers
C2.2.18 Rule 8: Consider Entropic Effect
C2.2.19 Gaining Binding by Reduction of Entropy
C2.2.20 Example of Ligand Rigidification C2.2.21 Making a Flexible Molecule More Rigid
C2.3 The Four Design Methods
C2.3.1 The Four Design Methods
C2.4 Analog Design
C2.4.1 Principles of Analog Design
C2.4.2 Example of Analog Design
C2.4.3 Additional Binding with Arginine Residue
C2.5 Database Searching
C2.5.1 3D Database Searching
C2.5.2 Scoring the Hits
C2.5.3 Advantages of Database Searching
C2.5.4 Problems of Conformational Complexity
C2.5.5 Assessing the Validity of the 3D Structures
C2.5.6 Example of Database Searching
C2.5.7 Limitations in Database Approaches
C2.5.8 Unexpected Binding Mode of Haloperidol
C2.5.9 Databases of Molecules in 3D
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C2.5.10 The Main Purpose of a 3D-Database Search
C2.6 De-Novo Design
C2.6.1 Automated Construction Approaches
C2.6.2 Molecule Generated by an Automated Method
C2.7 Manual Design
C2.7.1 Manual Design
C2.7.2 Importance of Visualization
C2.7.3 Tools in Manual Design
C2.7.4 Fully Exploiting the Fruits of the Analyses
C2.7.5 Design of a Hybrid Molecule
C2.8 Another Iteration
C2.8.1 Another Round of Analysis & Design
C2.9 A Success Story
C2.9.1 Example of Successful Structure-Based Design
C2.9.2 Mechanism of Action of the HIV-1 Protease
C2.9.3 The Crystallographic Structure of the HIV-1 Protease
C2.9.4 Hydrophobic Cavity of the HIV-1 Protease
C2.9.5 Flap of the HIV-1 Protease
C2.9.6 Transition State Concept for the Design of Inhibitors
C2.9.7 Topography of the Active Site of the Enzyme
C2.9.8 The MVT-101 Inhibitor
C2.9.9 Crystallographic Resolution of the HIV-1 Protease
C2.9.10 X-ray of the Complex of MVT-101 with the Enzyme (1/3)
C2.9.11 X-ray of the Complex of MVT-101 with the Enzyme (2/3)
C2.9.12 X-ray of the Complex of MVT-101 with the Enzyme (3/3)
C2.9.13 Design of Peptide-Like Structures
C2.9.14 Optimization to Fit the hydrophobic pockets
C2.9.15 Example of Optimized Structure
C2.9.16 X-ray Structure of the A-77003 Complex (1/4)
C2.9.17 X-ray Structure of the A-77003 Complex (2/4)
C2.9.18 X-ray Structure of the A-77003 Complex (3/4)
C2.9.19 X-ray Structure of the A-77003 Complex (4/4)
C2.9.20 A Drug Design Solution Using Database Searching
C2.9.21 The Terphenyl Hit
C2.9.22 In Depth Analysis of the Hit
C2.9.23 Incorporating Binding Features of the Water Molecule
C2.9.24 Rigidification of the Linear Inhibitor
C2.9.25 Considerations for Specificity
C2.9.26 Design of Cyclohexanone Scaffold
C2.9.27 The Design of Cyclic Ureas
C2.9.28 Limitation of the 6-Membered Ring Scaffold
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C2.9.29 The 7-Membered cyclic Urea Scaffold
C2.9.30 Design of the Cyclic Urea XK-263
C2.9.31 The Crystallographic Structure of XK-263 Complex (1/3)
C2.9.32 The Crystallographic Structure of XK-263 Complex (2/3)
C2.9.33 The Crystallographic Structure of XK-263 Complex (3/3) C2.9.34 Lessons From HIV-1 Protease Inhibition
C2.10 Conclusion
C2.10.1 Conclusion
C2.11 CHAPTER QUIZZES (Available only in Academic License)
C3. MOLECULAR DOCKING: PRINCIPLES AND METHODS
C3.1 Introduction to Computational Docking
C3.1.1 Molecular Recognition
C3.1.2 Molecular Recognition Process: Molecular Docking
C3.1.3 Understanding Molecular Recognition
C3.1.4 Molecular Docking Models
C3.1.5 The Lock and Key Theory
C3.1.6 The Induced-Fit Theory C3.1.7 The Conformation Ensemble Model
C3.1.8 From the Lock and Key to the Ensemble Model
C3.1.9 Experimental Methods to Study Molecular Docking
C3.1.10 Limitations of Experimental Techniques
C3.1.11 A Bottleneck in Drug Discovery
C3.1.12 Triggering the Computational Docking Discipline
C3.1.13 Definition of Computational Docking
C3.1.14 Applications of Computational Docking
C3.2 The Docking Problem
C3.2.1 The Docking Problem
C3.2.2 Great Diversity of Molecular Interactions
C3.2.3 Atomic Basis of Molecular Recognition
C3.2.4 Definition of the "Pose"
C3.2.5 Docking Viewed as a Black Box
C3.2.6 Current Computational Docking Programs
C3.2.7 Simulation and non-Simulation Approaches
C3.2.8 Simulation Approaches
C3.2.9 Non-Simulation Approaches
C3.2.10 Molecular Complementarity in Computational Docking
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C3.2.11 Shape Complementarity
C3.2.12 Chemical Complementarity
C3.2.13 Energy Dictates Molecular Associations
C3.2.14 Find a Complex that Minimizes the Energy
C3.2.15 Accounting for Molecular Flexibility in Docking C3.2.16 Flexible Docking: Increasing Levels of Complexity
C3.2.17 Initial Data and Nature of the Docking Difficulty
C3.2.18 Bound Docking
C3.2.19 Unbound Docking
C3.2.20 Modeled Docking
C3.2.21 The Three Generations in Computational Docking
C3.2.22 Three Components of Docking Software
C3.3 System Representation
C3.3.1 Molecular Representation C3.3.2 Atomic Representation
C3.3.3 Complexity of the Atomic Repesentation
C3.3.4 Internal Coordinates
C3.3.5 Protein Preparation
C3.3.6 Small Molecule Preparation
C3.3.7 Surface Representation
C3.3.8 Molecular Surface Matching
C3.3.9 Surface-Based Representation
C3.3.10 Accessible Surface Area
C3.3.11 Solvent Contact & Reentrant Surfaces C3.3.12 Example of Contact & Reentrant Surface
C3.3.13 Describing the Molecular Shape
C3.3.14 Connolly's Contact and Reentrant Surfaces
C3.3.15 Sparse Surface
C3.3.16 Delaunay Triangulation
C3.3.17 "Knob" and "Hole" Descriptors
C3.3.18 Using Knobs and Holes for Complementarity
C3.3.19 Other Examples of Shape Descriptors
C3.3.20 Grid Representation
C3.3.21 Use of GRID Potentials to Simplify the Docking C3.3.22 Assessing Shape Complementarity Using Grid
C3.4 Scoring Methods
C3.4.1 Need to Assess the Quality of Docked Complexes
C3.4.2 A Good Understanding of the Binding
C3.4.3 Important Questions
C3.4.4 Molecular Determinants for Binding
C3.4.5 Interaction Forces and Binding Energies
C3.4.6 Favorable Forces
C3.4.7 Unfavorable Forces
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C3.4.8 Desolvation Energies
C3.4.9 Entropic Effects
C3.4.10 Calculation of the Binding Energies
C3.4.11 Free Energy Equations
C3.4.12 Conversion of K to Energies C3.4.13 Difficulty of Calculating Free Energies of Binding ∆G
C3.4.14 Approximating ∆G by Molecular Mechanics
C3.4.15 Force-Field Calculations
C3.4.16 CHARMM Force Field to Score the Docking
C3.4.17 Approximating ∆G by Quantum Mechanics
C3.4.18 Development of Scoring Functions for Docking
C3.4.19 Scoring Functions
C3.4.20 Empirical Scoring Functions
C3.4.21 Example of Empirical Scoring Function
C3.4.22 Knowledge-Based Scoring Functions
C3.4.23 The Statistical Analyses
C3.4.24 Knowledge-Based Potentials
C3.4.25 The DrugScore Program
C3.4.26 DrugScore: The Thrombin Example
C3.4.27 Refinement of Scoring Functions
C3.4.28 Other Scoring Methods
C3.4.29 Shape and Property Complementarity Scoring
C3.4.30 Method to Measure Shape Complementarity
C3.4.31 Free Energy Perturbation
C3.5 Rigid Docking Methods
C3.5.1 Docking Algorithms
C3.5.2 The Mathematical Problem
C3.5.3 Two Docking Philosophies
C3.5.4 The Feature-Based Matching Approach
C3.5.5 Docking Using Feature-Based Methods
C3.5.6 Match Complementarity or Similarity Features
C3.5.7 Components of Feature-Based Matching Methods
C3.5.8 Step 1: Feature Extraction
C3.5.9 Step 2: Feature Matching C3.5.10 Step 3: Transformation (Assembly)
C3.5.11 Step 4: Filtering and Scoring
C3.5.12 Virtual Screening and De Novo Design
C3.5.13 Programs with Feature-Based Matching Methods
C3.5.14 Algorithms of Matching
C3.5.15 Clique-Search Based Approaches
C3.5.16 Goal of the Docking Algorithm
C3.5.17 Distance Compatibility Graph
C3.5.18 Clique Detection Methods
C3.5.19 Pose-Clustering C3.5.20 Searching for Compatible Triangles
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C3.5.21 Transformation that Align a Maximum of Triangles
C3.5.22 Complementarity and Similarity Matching
C3.5.23 Speed up of Pose-Clustering
C3.5.24 The Bottleneck of Pose-Clustering
C3.5.25 Geometric Hashing C3.5.26 Fast Retrieval of Matching Features
C3.5.27 Invariant Representation of Features
C3.5.28 Improvement of Pose-Clustering
C3.5.29 PatchDock Example
C3.5.30 The Stepwise Search Approach
C3.5.31 Components of a Stepwise Docking Program
C3.5.32 Exhaustive and Stochastic Search
C3.5.33 Exhaustive vs. Stochastic Search
C3.5.34 Exhaustive Search
C3.5.35 Mapped-Grid Method
C3.5.36 Physico-Chemical Properties of the Receptor
C3.5.37 Assessing Shape Complementarity
C3.5.38 Fast-Fourier Transform (FFT) Method
C3.5.39 FFT vs. Exhaustive Method
C3.5.40 FFT - Geometric Shape Complementarity
C3.5.41 FFT - Different Scores
C3.5.42 Docking of Plastocyanin and Cytochrome C
C3.5.43 Spherical Polar Fourier Correlations - Fast FFT
C3.5.44 Stochastic Algorithms
C3.5.45 A Typical Computational Docking Program
C3.5.46 Optimization Methods to Find the Best Solution
C3.5.47 Monte Carlo Methods
C3.5.48 Simulated Annealing
C3.5.49 Genetic Algorithms (GA)
C3.5.50 General Principle of GA
C3.5.51 Creating a New Generation
C3.5.52 Simulating the Reproduction Process
C3.5.53 Steps in Genetic Algorithms
C3.5.54 Lamarckian Genetic Algorithm
C3.5.55 Tabu Search
C3.5.56 Tabu Algorithm
C3.5.57 Avoiding Being Trapped in a Local Minimum
C3.5.58 Better Exploration of the Space
C3.5.59 The Hybrid Docking Method
C3.6 Methods for Incorporating Flexibility
C3.6.1 Implementation of Flexibility into Docking Software
C3.6.2 Degrees of Freedom in Flexible Docking
C3.6.3 Possible Classification of Methods for Flexibility
C3.6.4 Classification of Methods C3.6.5 Incorporating Small Molecule Flexibility
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C3.6.6 Modeling Small Molecules as Flexible Entities
C3.6.7 Small Molecule Flexibility
C3.6.8 Integration of Ligand Flexibility and Protein Structure
C3.6.9 Methods for Handling Ligand Flexibility Explicitly
C3.6.10 The Ensemble Docking Method C3.6.11 Advantage of the Ensemble Docking Method
C3.6.12 The FLOG Software
C3.6.13 Problem of the Ensemble Docking Approach
C3.6.14 The Improved Ensemble Docking Method
C3.6.15 Remove Redundancy in the Rigid Fragment
C3.6.16 Remove Redundancy in the Flexible Fragment
C3.6.17 Score: Sum of Atom Interactions
C3.6.18 Step-1: Conformational Analysis
C3.6.19 Step-2: Superimposition and Positioning
C3.6.20 Step-3: Conformational Analysis
C3.6.21 Dramatic Improvement in Computing Time
C3.6.22 Efficient Treatment of Clashes
C3.6.23 Validation of the Lorber-Shoichet Method
C3.6.24 Extension to Analog Compounds
C3.6.25 The Fragmentation Docking Method
C3.6.26 Place-and-Join Algorithm
C3.6.27 Principle of the Place-and-Join Method
C3.6.28 Difficulty of the Place and Join Method
C3.6.29 Incremental-Based Methods
C3.6.30 Incremental Algorithm
C3.6.31 Stochastic Search Methods
C3.6.32 GOLD Program
C3.6.33 Incorporating Protein Flexibility
C3.6.34 Importance of Modeling Protein Flexibility
C3.6.35 Historical Note
C3.6.36 Flexibility Through Soft Scoring Functions
C3.6.37 Reduce the Importance of Steric Clashes
C3.6.38 Soft Van der Waals Repulsion Functions
C3.6.39 Decreasing Van der Waals Radii
C3.6.40 Soft Electrostatic Repulsion Potentials
C3.6.41 Soft Scoring Functions in Protein-Protein Docking
C3.6.42 Implicit Flexibility in Protein-Protein Docking
C3.6.43 Problems with Soft Scoring
C3.6.44 Soft Scoring as a First Filtering Method
C3.6.45 Protein Side-Chains Flexibility
C3.6.46 Importance of Modeling Side-Chain Mobility
C3.6.47 Determine the Optimum Combination of Side-Chains
C3.6.48 Combinatorial Explosion
C3.6.49 Side Chain Rotamer Libraries
C3.6.50 From Folding to Docking
C3.6.51 The Leach Algorithm
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C3.6.52 Generation and Minimization of Complexes
C3.6.53 Other Optimization Methods
C3.6.54 Restricting Searches and Minimizations
C3.6.55 Identify Key Residues for the Interaction
C3.6.56 Restrict the Search to Exposed Side Chains C3.6.57 Backbone and Side Chain Flexibility
C3.6.58 Conventional Methods not Adapted
C3.6.59 The Multiple Protein Structure (MPS) Approach
C3.6.60 Principle of the MPS Approach
C3.6.61 Sources of Multiple Protein Structures
C3.6.62 MPS: a Good Model for the Recognition Process
C3.6.63 How the MPS are Exploited?
C3.6.64 Successive and Independent Docking Treatments
C3.6.65 Acetylcholinesterase Example
C3.6.66 The United Protein Approach
C3.6.67 Key Concept of FlexE
C3.6.68 Remove Redundant Information
C3.6.69 FlexE: Incompatibility Graph
C3.6.70 FlexE: Search & Scoring
C3.6.71 The Average Grid Approach
C3.6.72 Single Grid Combining MPS Information
C3.6.73 Scoring Tolerance with MPS-based Grids
C3.6.74 Average Grid Approach vs. Soft Scoring
C3.6.75 Dynamic Pharmacophore-Based Approach
C3.6.76 Dynamic Pharmacophore Model for HIV-1 Integrase
C3.6.77 Hybrid Pharmacophore Models using LigandScout
C3.6.78 Domain Movements
C3.6.79 Example of Calmodulin Domain Movements
C3.6.80 Conventional Modeling Methods are not Suited
C3.6.81 Intrinsic Flexibility
C3.6.82 Hinge-Bent Movements
C3.6.83 Automated Methods for Hinge Detection
C3.6.84 Incorporating Hinge-Bent Movements in Docking
C3.6.85 Docking with Hinge-Bent Movements
C3.6.86 Ball-and-Socket Motions
C3.7 Uses of Docking in Research
C3.7.1 Computational Docking in Drug Discovery
C3.7.2 Virtual Screening
C3.7.3 Lead Hopping
C3.7.4 Increasing HTS Hit Rates
C3.7.5 Confirm Choice of Prototype Structure
C3.7.6 Manual Design of a New Scaffold
C3.7.7 New Cores from a Database of Scaffolds
C3.7.8 De Novo Design of Spacers C3.7.9 Modulating Protein-Protein Interactions
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C3.7.10 Query for 3D Database Searching
C3.7.11 Creative Molecular Design Conditions
C3.7.12 Design of Combinatorial Libraries
C3.7.13 Understanding SAR
C3.7.14 Reducing Multiple Hypotheses to a Single One C3.7.15 Series Optimization
C3.7.16 Explaining Incomprehensible Observations
C3.7.17 Identifying Incorrect Working Hypotheses
C3.7.18 Align Chemically Unrelated Molecules in 3D
C3.7.19 Improving the Solubility of a Ligand
C3.7.20 Understand the Intrinsic Limitations of a Scaffold
C3.7.21 Assessing the Potential of a Hit
C3.7.22 Elucidating Exact Mode of Action
C3.7.23 Assessing Multiple Alignment Hypotheses
C3.7.24 Molecular Mimicry
C3.7.25 Computational Validation of Hypotheses
C3.8 Docking Softwares
C3.8.1 Docking Programs
C3.8.2 Dock
C3.8.3 Autodock
C3.8.4 DockVision
C3.8.5 DockIt
C3.8.6 FlexX
C3.8.7 Ligin C3.8.8 FT-Dock
C3.8.9 GOLD
C3.8.10 GRAMM
C3.8.11 Hex
C3.8.12 eHiTS
C3.8.13 LigandFit
C3.8.14 FRED
C3.8.15 Glide
C3.8.16 Which Software is Better?
C3.9 Future and Perspectives
C3.9.1 Limitations in Computational Docking
C3.9.2 Trade Off Between Efficiency and Accuracy
C3.9.3 Screening Large Chemical Libraries
C3.9.4 A Two Step Strategy
C3.9.5 High-throughput Docking Using Grid-Computing
C3.9.6 How Does it Work?
C3.9.7 Wide In Silico Docking On Malaria (WISDOM)
C3.9.8 Enrichment Factor
C3.9.9 Current Status of the Docking Problem
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C3.9.10 The Docking Bottlenecks
C3.9.11 More Effective Scoring Functions
C3.9.12 Modeling the Solvent
C3.9.13 Validation of Scoring Functions
C3.9.14 Target Trainable Scoring Functions C3.9.15 Database of Decoys
C3.9.16 Consensus Scoring
C3.9.17 The Molecular Flexibility Challenge
C3.9.18 Developing Better Models of Flexibility
C3.9.19 Importance of Visual Docking
C3.9.20 Requirement for Manual Docking
C3.9.21 Illustration of Manual Docking
C3.9.22 Manual Docking with Solid Models
C3.9.23 Virtual Reality Docking System
C3.9.24 Example of Docking using CAVE
C3.9.25 Synergy Between Interactive & Automated Docking
C3.9.26 Interactive Computer-Guided Docking
C3.9.27 Protein-Protein Docking Benchmarks
C3.9.28 The CAPRI Competition
C3.9.29 Six Weeks for Submitting Predicted Complexes
C3.9.30 Assessment of the Predictions
C3.9.31 A New CAPRI Scoring Category
C3.9.32 CAPRI History and Experience
C3.9.33 Perspectives
C3.10 CHAPTER QUIZZES (Available only in Academic License)
C4. CASE STUDIES IN STRUCTURE-BASED DESIGN
C4.1 Case Study-1 : Phenyl Imidazoles
C4.1.1 Phenyl-Imidazoles Inhibit Cytochrome P450
C4.1.2 Simple Consideration: Shape Similarity
C4.1.3 Perhaps Binding Elements are more Complex ?
C4.1.4 The Structure-Based Answer
C4.1.5 Phenyl-Imidazole Browser
C4.1.6 Limitations of Chemical Intuition
C4.2 Case Study-2 : BACE-1 Inhibitors
C4.2.1 BACE-1 Inhibitors
C4.2.2 Screening the J&J Corporate Compound Collection
C4.2.3 Structural Determinants of the Biological Activity of 1 C4.2.4 X-ray Structure of the Complex of 1 with BACE-1
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C4.2.5 Flap Flexibility in Aspartyl Proteases
C4.2.6 Compound with Increased Folding Capability
C4.2.7 How to Gain Additional Binding
C4.2.8 Design of a More Potent Inhibitor
C4.2.9 X-Ray Structure of the Complex with 3a C4.2.10 Pharmacological Action of Compound 3a
C4.2.11 Important Structural Determinants for Binding
C4.2.12 Summary
C4.3 Case Study-3 : Factor Xa Inhibitors
C4.3.1 Therapeutic Utility of Factor Xa Inhibitors
C4.3.2 DX-9065a : a Factor Xa Inhibitor
C4.3.3 Complex Between Factor Xa and DX-9065a
C4.3.4 Analysis of the Factor Xa and DX-9065a Complex (1/4)
C4.3.5 Analysis of the Factor Xa and DX-9065a Complex (2/4) C4.3.6 Analysis of the Factor Xa and DX-9065a Complex (3/4)
C4.3.7 Analysis of the Factor Xa and DX-9065a Complex (4/4)
C4.3.8 Role of the Carboxylic Acid in Selectivity (1/3)
C4.3.9 Role of the Carboxylic Acid in Selectivity (2/3)
C4.3.10 Role of the Carboxylic Acid in Selectivity (3/3)
C4.3.11 Initial Inhibitor Design
C4.3.12 Design (step 1): Structural Moiety for Pocket S1
C4.3.13 Phenyl-Amidine Entered into the S1 Pocket
C4.3.14 Phenyl-Amidine Oriented in Lowest Energy Orientation
C4.3.15 Design (step 2): Structural Moiety for Pocket S4 C4.3.16 Phenyl Ring Introduced in Pocket S4
C4.3.17 Phenyl Substituted with an Amidine
C4.3.18 Stacking Interaction of Phenyl-Amidine with Trp-215
C4.3.19 Phenyl-Amidine Orientation
C4.3.20 Design (step 3): Design of the Spacer
C4.3.21 Phenyl-Amidine Groups in their Preferred Orientations
C4.3.22 Spacer with three Atoms
C4.3.23 Candidate Prototype in the Catalytic Site
C4.3.24 Design (step 4): Positioning of the Carboxylate
C4.3.25 Discovery of a Lead Compound C4.3.26 Optimization of the Designed Series
C4.3.27 Interaction of Compound 21 with Factor Xa
C4.3.28 Finding an Optimal Spacer
C4.4 Case Study-4 : Kinase Inhibitors
C4.4.1 Pyrrolo-Pyrimidine & Quinazoline EGF-R Inhibitors
C4.4.2 Novartis and Parke-Davis Opposite Binding Models
C4.4.3 Controversy: Novartis & Parke-Davis Binding Modes
C4.4.4 Parke-Davis Analyses
C4.4.5 Novartis Analyses
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C4.4.6 X-ray Structure of ATP Bound to a Kinase
C4.4.7 Binding Mode of ATP
C4.4.8 Binding Mode of Staurosporine
C4.4.9 Homology Model of EGF-R Catalytic Site
C4.4.10 From Staurosporine to Pyrrolo-pyrimidine C4.4.11 The Novartis Binding Mode of Pyrrolo-pyrimidine
C4.4.12 The Pyrrole Ring in the Large Pocket
C4.4.13 The Pyrrole Ring Pointing Towards the Sugar Pocket
C4.4.14 Parke-Davis Analyses the Quinazoline Scaffold
C4.4.15 Additional SAR Analyses made by Parke-Davis
C4.4.16 Parke-Davis Model of the Quinazoline Analogs
C4.4.17 Specificity Observed in EGF-R Kinase Inhibition
C4.4.18 Anilino Towards the Sugar Pocket not Reasonable
C4.4.19 Parke-Davis Model Consistent with Observed SAR
C4.4.20 Binding Mode of the Pyrrolo-Pyrimidine Series
C4.4.21 Binding Mode of the Quinazoline Series
C4.4.22 What is the Correct Solution?
C4.4.23 Ligand Observed with a Novartis Binding Mode
C4.4.24 Alignment with the Novartis Model
C4.4.25 Ligand Observed with a Parke-Davis Binding Mode
C4.4.26 Alignment with the Parke-Davis Model
C4.4.27 X-Ray Resolution of Tarceva Bound to EGF-R Kinase
C4.4.28 Conclusion
C4.5 ADDITIONAL CASE STUDIES
C4.5.1 Additional Case Studies
C5. CASE STUDIES OF DOCKING IN DRUG DISCOVERY
C5.1 Case Study 1 : Pyrimidin-4-yl-ureas for Kinase Inhibition
C5.1.1 Inhibitor Active on Several Protein Kinases
C5.1.2 Structural Determinants for the Activity
C5.1.3 Correlation with the Volume of Gate Keeper Residue
C5.1.4 Outcome of this Study
C5.2 Case Study 2 : Inhibition of CHK1
C5.2.1 The CHK1 Kinase
C5.2.2 The Indazole Series
C5.2.3 Binding Mode of the Indazole Core
C5.2.4 Binding Modes of the Potent Indazole Analog C5.2.5 Pocket may Help for Selectivity
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C5.2.6 Overlay with Other Chk1 Inhibitors
C5.2.7 Structure-Based Screening of Chk1 Inhibitors
C5.2.8 Hits Identified by Virtual Screening
C5.2.9 X-Ray Structures of Four Virtual Screening Hits
C5.2.10 Binding Modes Predicted for Other Five Hits C5.2.11 Outcome of this Study
C5.3 Case Study 3 : Thrombin Inhibitors
C5.3.1 Two Methods of Virtual Screening
C5.3.2 Combining Structure-Based and Ligand-Based VS
C5.3.3 Screening Protocol
C5.3.4 Steps of the Docking Treatment
C5.3.5 Specificity Pockets in Thrombin
C5.3.6 Development of the Hybrid Approach
C5.3.7 Inhibition Assays of Top-Scoring Compounds C5.3.8 Analysis of the Binding Mode of Compound 1
C5.3.9 Binding Mode Compared with Known Inhibitors
C5.3.10 What was Learned in this Test Study ?
C5.3.11 Analyzing Top Ranked Compounds
C5.3.12 Limitations of Scoring Functions
C5.4 Case Study 4 : Salicylamide Renin Inhibitor
C5.4.1 Search for New Scaffold in Renin Inhibition
C5.4.2 3D Analyses
C5.4.3 Preferred Location of Phenyl Ring in Pocket P3
C5.4.4 Docking Experiment
C5.4.5 Results of the Docking
C5.4.6 Search for an Optimal Spacer
C5.4.7 The Salicylamide Lead
C5.4.8 Predictions Confirmed by X-Ray Study
C5.4.9 Browser of Salicylamide Inhibitor
C5.4.10 Optimization of the Salicylamide Series
C5.4.11 Summary
C5.4.12 Lead Hopping
C5.5 Case Study 5 : Inhibition of Human Neutrophil Elastase
C5.5.1 Inhibition of Human Neutrophil Elastase
C5.5.2 Sesquiterpene Lactones
C5.5.3 Studies on 17 Sesquiterpene Lactones
C5.5.4 Docking Studies
C5.5.5 Docking Protocol
C5.5.6 Results of the Docking Studies
C5.5.7 Elucidation of the Mode of Action
C5.5.8 Docking Results of Melampolides 2 and 4 C5.5.9 Docking Results of Podachaenin 14
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C5.5.10 Docking Results of Germacranolide 8
C5.5.11 Structural Determinants for Binding to HNE
C5.5.12 Summary
C5.6 ADDITIONAL CASE STUDIES
C5.6.1 Additional Case Studies
C6. ANALYSES OF PROTEIN-LIGAND COMPLEXES
C6.1 Elastase Inhibitors
C6.1.1 Therapeutic Utility of Elastase Inhibitors
C6.1.2 Analysis of the HLE Active Site (1/3)
C6.1.3 Analysis of the HLE Active Site (2/3)
C6.1.4 Analysis of the HLE Active Site (3/3)
C6.1.5 Complex of MSACK with HLE
C6.1.6 Analysis of the Binding of MSACK (1/3)
C6.1.7 Analysis of the Binding of MSACK (2/3)
C6.1.8 Analysis of the Binding of MSACK (3/3)
C6.1.9 The Design of a New Elastase Inhibitor
C6.1.10 Complex of Inhibitor with PPE Elastase
C6.1.11 Binding of Aminopyrimidone Candidate (1/4)
C6.1.12 Binding of Aminopyrimidone Candidate (2/4)
C6.1.13 Binding of Aminopyrimidone Candidate (3/4)
C6.1.14 Binding of Aminopyrimidone Candidate (4/4)
C6.2 Thymidylate Synthase Inhibitors
C6.2.1 The Thymidylate Synthase Enzyme
C6.2.2 The Thymidylate Synthase Active Site
C6.2.3 The Thymidylate Synthase Catalytic Mechanism
C6.2.4 Two Possible Strategies for Inhibiting TS C6.2.5 Inhibition by Binding to the TS Substrate Site
C6.2.6 X-Ray of TS with 5-FdUMP and Cofactor
C6.2.7 Inhibition by Binding to Cofactor Site
C6.2.8 Complex of CB3717 with Thymidylate Synthase
C6.2.9 Analysis of the Binding of CB3717 (1/4)
C6.2.10 Analysis of the Binding of CB3717 (2/4)
C6.2.11 Analysis of the Binding of CB3717 (3/4)
C6.2.12 Analysis of the Binding of CB3717 (4/4)
C6.2.13 Design of a New TS Inhibitor
C6.2.14 The Quinazolinone Scaffold C6.2.15 One Atom Spacer
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C6.2.16 The Glutamic Acid Component
C6.2.17 Designed and Reference Molecules in 3D
C6.3 Inhibitors of Phospholipase A-2
C6.3.1 Phospholipase A2
C6.3.2 PLA2 Transition State Analogues
C6.3.3 Complex of an Inhibitor with PLA2
C6.3.4 Analysis of the Binding of the Inhibitor (1/4)
C6.3.5 Analysis of the Binding of the Inhibitor (2/4)
C6.3.6 Analysis of the Binding of the Inhibitor (3/4)
C6.3.7 Analysis of the Binding of the Inhibitor (4/4)
C6.3.8 Design of a New Class of PLA2 Inhibitors
C6.3.9 Binding of Acenaphthene with PLA2
C6.4 Thrombin Inhibitors
C6.4.1 Therapeutic Utility of Thrombin Inhibitors
C6.4.2 Examples of Thrombin Inhibitors
C6.4.3 The Catalytic Mechanism of Thrombin
C6.4.4 The "Ser-His-Asp" Catalytic Triad
C6.4.5 First Step: Transfer of H from the Ser to the His
C6.4.6 Second Step: Tetrahedral Intermediate
C6.4.7 Third Step: Binding to the Oxyanion Hole
C6.4.8 Final Step: The Peptide Bond is Cleaved
C6.4.9 The Product of the Reaction
C6.4.10 Reaction-Intermediate-Based Inhibitors
C6.4.11 Another Class of Potent Thrombin Inhibitors
C6.4.12 The Complex of Thrombin with NAPAP
C6.4.13 Analysis of the NAPAP-Thrombin Complex (1/5)
C6.4.14 Analysis of the NAPAP-Thrombin Complex (2/5)
C6.4.15 Analysis of the NAPAP-Thrombin Complex (3/5)
C6.4.16 Analysis of the NAPAP-Thrombin Complex (4/5)
C6.4.17 Analysis of the NAPAP-Thrombin Complex (5/5)
C6.4.18 The Design of a New Thrombin Inhibitor
C6.5 Human Rhinovirus Inhibitors
C6.5.1 Inhibition of Human Rhinovirus Protein
C6.5.2 The Mechanism of Action of WIN54954
C6.5.3 Complex of WIN54954 with Rhinovirus HRV14
C6.5.4 Binding of WIN54954 with Rhinovirus HRV14 (1/6)
C6.5.5 Binding of WIN54954 with Rhinovirus HRV14 (2/6)
C6.5.6 Binding of WIN54954 with Rhinovirus HRV14 (3/6)
C6.5.7 Binding of WIN54954 with Rhinovirus HRV14 (4/6)
C6.5.8 Binding of WIN54954 with Rhinovirus HRV14 (5/6)
C6.5.9 Binding of WIN54954 with Rhinovirus HRV14 (6/6) C6.5.10 Optimization of WIN54954
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C6.6 Rotamase Inhibitors
C6.6.1 Utility of Rotamase Inhibitors
C6.6.2 Complex of FK506 with FKBP
C6.6.3 Analysis of the Binding of FK506 (1/4) C6.6.4 Analysis of the Binding of FK506 (2/4)
C6.6.5 Analysis of the Binding of FK506 (3/4)
C6.6.6 Analysis of the Binding of FK506 (4/4)
C6.6.7 Design of a New Rotamase Inhibitor
C6.6.8 The Pipecolyl Inhibitor Mimics FK506
C6.6.9 Binding of the Pipecolyl Inhibitor (1/3)
C6.6.10 Binding of the Pipecolyl Inhibitor (2/3)
C6.6.11 Binding of the Pipecolyl Inhibitor (3/3)
C6.7 Renin Inhibitors
C6.7.1 Therapeutic Utility of Renin Inhibitors
C6.7.2 The Design of Renin Inhibitors
C6.7.3 Complex of Statine with Rhizopuspepsin
C6.7.4 Analysis of the Binding of Statine (1/3)
C6.7.5 Analysis of the Binding of Statine (2/3)
C6.7.6 Analysis of the Binding of Statine (3/3)
C6.7.7 Design of a Macrocyclic Renin Inhibitor
C6.7.8 Inaccuracies in Homology Models
C6.8 Inhibitors of PNP
C6.8.1 The Purine Nucleoside Phosphorylase Protease
C6.8.2 Therapeutic Utility of PNP Inhibitors
C6.8.3 The Complex of Guanine with PNP
C6.8.4 Analysis of the Active Site of PNP (1/2)
C6.8.5 Analysis of the Active Site of PNP (2/2)
C6.8.6 Strategy for the Design of PNP Inhibitors
C6.8.7 Design of 9-Deazaguanine Derivatives
C6.8.8 Binding of 9-Deaza-Guanine Candidate (1/3)
C6.8.9 Binding of 9-Deaza-Guanine Candidate (2/3)
C6.8.10 Binding of 9-Deaza-Guanine Candidate (3/3)
C6.8.11 Browser of PNP Inhibitors
C6.9 Intercalating Antibiotics
C6.9.1 Therapeutic Utility of Intercalating Agents
C6.9.2 Daunorubicin a Potent Anthracycline Antibiotic
C6.9.3 Prerequisite for Antibiotic Activity
C6.9.4 Complex of Daunorubicin with a Hexanucleotide
C6.9.5 Analysis of the Binding of Daunorubicin (1/5)
C6.9.6 Analysis of the Binding of Daunorubicin (2/5) C6.9.7 Analysis of the Binding of Daunorubicin (3/5)
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C6.9.8 Analysis of the Binding of Daunorubicin (4/5)
C6.9.9 Analysis of the Binding of Daunorubicin (5/5)
C6.9.10 Design of Novel Intercalating Agents
C6.10 Dihydrofolate Reductase Inhibitors
C6.10.1 Utility of Dihydrofolate Reductase Inhibitors
C6.10.2 Complex of Methotrexate with DHFR
C6.10.3 Binding Mode of Methotrexate with DHFR (1/5)
C6.10.4 Binding Mode of Methotrexate with DHFR (2/5)
C6.10.5 Binding Mode of Methotrexate with DHFR (3/5)
C6.10.6 Binding Mode of Methotrexate with DHFR (4/5)
C6.10.7 Binding Mode of Methotrexate with DHFR (5/5)
C6.10.8 Trimethoprim: a DHFR Inhibitor
C6.10.9 The Design of a Novel DHFR-Inhibitor
C6.10.10 Complex of Brodimoprim with DHFR C6.10.11 Binding of Brodimoprim with DHFR (1/2)
C6.10.12 Binding of Brodimoprim with DHFR (2/2)
C6.11 Sialidase Inhibitors
C6.11.1 The Sialidase Enzyme
C6.11.2 Therapeutic Utility of Sialidase Inhibitors
C6.11.3 Complex of Sialic Acid with Sialidase
C6.11.4 Analysis of Sialic Acid Binding (1/4)
C6.11.5 Analysis of Sialic Acid Binding (2/4)
C6.11.6 Analysis of Sialic Acid Binding (3/4)
C6.11.7 Analysis of Sialic Acid Binding (4/4)
C6.11.8 The Design of a Potent Sialidase Inhibitor
C6.12 ADDITIONAL CASE STUDIES
C6.12.1 Additional Case Studies
C6.13 CHAPTER QUIZZES (Available only in Academic License)
D. MOLECULAR BASIS OF DRUGS
D1. MOLECULAR GEOMETRY
D1.1 2D/3D
D1.1.1 Molecules Considered as 2D Structures
D1.1.2 The Three-Dimensional Shape of a Molecule
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D1.1.3 2D and 3D Representations
D1.1.4 A Molecule: An Assembly of Atoms in 3D
D1.1.5 Molecular Lego
D1.1.6 Molecular Fragments for Constructing Molecules
D1.2 Conformers
D1.2.1 A Molecule is a Flexible Entity
D1.2.2 Conformation Definition
D1.2.3 Example of Conformations of a Molecule
D1.2.4 Bioactive Conformation
D1.3 Torsion Angles
D1.3.1 Interconversion Between Conformers
D1.3.2 How Do Interconversions Occur?
D1.3.3 Definition of the Conformers of a Molecule
D1.3.4 The Torsion Angle Concept
D1.3.5 Definition of Torsion Angles
D1.3.6 Monitoring Torsion Angles
D1.3.7 Newman Projections and Torsion Angles
D1.3.8 Convention for the Sign of Torsion Angles
D1.3.9 Ring Conformations
D1.4 Conformational Complexity
D1.4.1 Rigid and Flexible Molecules D1.4.2 Codeine and Fenoxedil
D1.4.3 Monitoring Torsion Angle Combinations
D1.4.4 Conformational Explosion
D1.5 Ratio of Conformers
D1.5.1 Mixtures of Conformers
D1.5.2 Ratio of Conformers and Population
D1.6 CHAPTER QUIZZES (Available only in Academic License)
D2. MOLECULAR PROPERTIES
D2.1 Introduction
D2.1.1 Properties of a Molecule
D2.1.2 Average of a Conformational-Dependent Property
D2.1.3 Importance of the 3D Molecular Geometries
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D2.2 Biological Properties
D2.2.1 Biological Properties of Proteins
D2.2.2 Biological Properties of Chiral Analgesics
D2.3 Physical Properties
D2.3.1 Physical Properties
D2.3.2 Calculation of Other Physical Properties
D2.4 Chemical Properties
D2.4.1 Chemical Properties
D2.4.2 Enolization of Keto-3 Steroids
D2.4.3 Relative Stability of Isomers
D2.4.4 Relative Stability of the two Isomers of Trans-Octalin
D2.4.5 Geometrical Preference Explains Enolization
D2.4.6 Reactivity of Alkyl Halides
D2.4.7 SN2 Mechanism
D2.4.8 E2 Elimination Mechanism
D2.4.9 Molecular Geometries and Chemical Properties
D2.5 Many Properties
D2.5.1 Many Properties of a Molecule
D2.6 CHAPTER QUIZZES (Available only in Academic License)
D3. STEREOCHEMISTRY
D3.1 Introduction
D3.1.1 Introduction on Stereochemistry
D3.1.2 Bond Lengths D3.1.3 Bond Multiplicity
D3.1.4 Atom Size
D3.1.5 Electronegativity
D3.1.6 Hybridization
D3.1.7 Bond Angles
D3.1.8 Thorpe-Ingold Effect
D3.1.9 Torsion Angles
D3.1.10 Torsion Angle Sign Convention
D3.1.11 Examples of Torsion Angles
D3.1.12 Torsion Angle Descriptor (sp3-sp3) D3.1.13 Torsion Angle Descriptor (sp2-sp3)
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D3.2 Chirality
D3.2.1 Chirality
D3.2.2 Example 1
D3.2.3 Example 2 D3.2.4 Chirality Descriptor: Optical Rotation
D3.2.5 Chirality Nomenclature
D3.2.6 The Order of Priority (1/5)
D3.2.7 The Order of Priority (2/5)
D3.2.8 The Order of Priority (3/5)
D3.2.9 The Order of Priority (4/5)
D3.2.10 The Order of Priority (5/5)
D3.2.11 Examples of R/S Assignments (1/4)
D3.2.12 Examples of R/S Assignments (2/4)
D3.2.13 Examples of R/S Assignments (3/4)
D3.2.14 Examples of R/S Assignments (4/4)
D3.2.15 The Newman Projection
D3.2.16 The Fischer Projection (1/3)
D3.2.17 The Fischer Projection (2/3)
D3.2.18 The Fischer Projection (3/3)
D3.2.19 Chirality: D/L
D3.2.20 D-alanine
D3.2.21 L-alanine
D3.2.22 Chirality: Erythro/Threo
D3.2.23 Threo
D3.2.24 Erythro
D3.2.25 Other Examples of Chiral Molecules: Example 1
D3.2.26 Example 2 of Chiral Molecule
D3.2.27 Example 3 of Chiral Molecule
D3.2.28 Example 4 of Chiral Molecule
D3.2.29 Example 5 of Chiral Molecule
D3.2.30 Example 6 of Chiral Molecule
D3.3 Double Bonds
D3.3.1 Cis-Trans Stereochemistry of Double Bonds D3.3.2 E/Z Stereochemistry of Double Bonds
D3.3.3 s-cis/s-trans Conformations
D3.3.4 Re/Si Nomenclature of the Faces of Double Bonds
D3.4 Rings
D3.4.1 Rings
D3.4.2 Chair
D3.4.3 Boat
D3.4.4 Twist Boat
D3.4.5 Crown
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D3.4.6 Rings: Axial and Equatorial Orientations
D3.5 Symmetry
D3.5.1 Introduction on Symmetry Operations
D3.5.2 Symmetry C2
D3.5.3 Symmetry C3
D3.5.4 Symmetry Sigma
D3.5.5 Inversion (i)
D3.5.6 Example of Inversion
D3.5.7 Rotatory Reflection (Sn)
D3.6 CHAPTER QUIZZES (Available only in Academic License)
D4. MOLECULAR ENERGIES
D4.1 Introduction
D4.1.1 Internal Energy of a Molecule
D4.1.2 Internal Energy Associated to a Conformation
D4.1.3 Transition State
D4.1.4 Potential Surface
D4.1.5 Thermodynamics & Kinetics
D4.2 Thermodynamics
D4.2.1 Thermodynamics: Conformer Populations
D4.2.2 Thermodynamics: Boltzmann Equation
D4.2.3 Boltzmann Population Analysis for Two Conformers
D4.2.4 Boltzmann Population Analysis for 3 Conformers
D4.2.5 Thermodynamics: Cyclohexane Example
D4.2.6 Populations of Twisted-Boat and Chair Conformers
D4.2.7 Thermodynamics: Methylcyclohexane Example
D4.3 Kinetics
D4.3.1 Kinetics
D4.3.2 Kinetics: Arrhenius Equation
D4.3.3 Kinetics: Arrhenius Graph
D4.3.4 Kinetics Ethane Example
D4.3.5 Torsional Barrier in Ethane
D4.3.6 Kinetics Cyclohexane Example
D4.3.7 Interconversion Barrier in Cyclohexane
D4.3.8 Kinetics Amide Bond Example D4.3.9 Amide Barrier Crossed Every 10 Seconds
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D4.4 Molecular Modeling
D4.4.1 Molecular Modeling
D4.4.2 Example of Kinetic or Thermodynamic Control
D4.4.3 Interconversion Between the Two Forms D4.4.4 Lowering the Energy of the Transition State
D4.4.5 Interconversion Between the Two Forms
D4.4.6 Raising the Energy of the Transition State
D4.4.7 Interconversion Between the Two Forms
D4.4.8 Modifying Conformers Populations
D4.4.9 Repulsions More Important in the Boat Form
D4.4.10 Tropane is Found Only in a Chair Conformation
D4.4.11 Example of Atropisomerism
D4.4.12 Molecular Energies: The Key of Molecular Modeling
D4.5 Modeling in Drug Design
D4.5.1 Molecular Modeling in Drug Design
D4.5.2 Importance of Energies: the Morphinan Example
D4.5.3 Morphinan and D-nor Morphinan Alignment
D4.5.4 Conformational Analysis of Morphinan
D4.5.5 Conformational Analysis of D-nor Morphinan
D4.5.6 A Rationale for Explaining the Activities Observed
D4.5.7 Morphinan: Validation and Design
D4.5.8 Preferred Conformer of Active Enantiomer
D4.5.9 Preferred Conformer of Inactive Enantiomer D4.5.10 Restoring Activities to the Inactive Analog?
D4.5.11 Morphinan Browser
D4.5.12 What We Can Learn From The Morphinan Example
D4.6 How to Calculate Energies
D4.6.1 The Need of Tools for Calculating Energies
D4.6.2 Two Methods for Calculating Energies
D4.7 Quantum Mechanics
D4.7.1 Calculation of Energies by the Schrodinger Equation
D4.7.2 Ab-Initio and Semi-empirical Calculations
D4.7.3 Calculation of Energies
D4.7.4 The Density Function Theory
D4.7.5 The Choice of a Method
D4.8 Molecular Mechanics
D4.8.1 Molecular Mechanics
D4.8.2 Force-Field
D4.8.3 Force Field Components
D4.8.4 Bond Lengths: Stretching Contributions
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D4.8.5 Function
D4.8.6 Examples of Elementary Stretching Contributions
D4.8.7 Bond Angles: Bending Contributions
D4.8.8 Function
D4.8.9 Examples of Elementary Bending Contributions D4.8.10 Torsion Angles: Torsional Contributions
D4.8.11 Function
D4.8.12 Examples of Elementary Torsional Contributions
D4.8.13 Van der Waals Interactions
D4.8.14 Function
D4.8.15 Examples of Elementary Van der Waals
D4.8.16 Electrostatic Dipolar Contributions
D4.8.17 Function
D4.8.18 Examples of Elementary Electrostatic Contributions
D4.8.19 Hydrogen Bond Energy Contributions
D4.8.20 Function
D4.8.21 Examples of Elementary Hydrogen Bond Contributions
D4.8.22 Total Energy in a Force Field Calculation
D4.8.23 Main Force Fields
D4.8.24 What One Should Remember
D4.8.25 Relative Energies
D4.9 CHAPTER QUIZZES (Available only in Academic License)
D5. CONFORMATIONAL ANALYSIS
D5.1 Introduction
D5.1.1 Geometries, Energies and Conformational Analysis
D5.1.2 Energy Profile: a Global Information
D5.1.3 Definition of Conformational Analysis
D5.2 Potential Surface
D5.2.1 Conformational Potential Surface: One Rotation
D5.2.2 Conformational Potential Surface: Two Rotations
D5.2.3 Energy Profile Viewed from the Top
D5.2.4 Energy Profile Viewed as Contour Lines
D5.2.5 Conformational Potential Surface
D5.2.6 Special Forms
D5.2.7 Interconversion Between Conformers
D5.2.8 Energy Barriers
D5.2.9 Interconversion Pathway
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D5.3 Conformational Analysis
D5.3.1 Conformational Analysis Principles
D5.3.2 Systematic Scanning of All Potential Surfaces
D5.3.3 Systematic Scanning is Time Consuming D5.3.4 How to Reduce Conformational Search?
D5.3.5 One Conformer Represents a Whole Family
D5.3.6 Working with a Set of Representative Conformers
D5.3.7 Sildenafil Example
D5.3.8 Family Representatives: Small Rings
D5.3.9 Family Representatives: Acyclic Bonds
D5.3.10 Consequence: Minimization Treatments
D5.3.11 Example: Analysis of Elementary Fragments
D5.3.12 Example: Generation of Representative Conformers
D5.3.13 Example: Results of Conformational Analysis
D5.3.14 Conformational Analysis Principles: Summary
D5.4 Minimizations
D5.4.1 Definition of the Minimization of a Conformer
D5.4.2 Improved Geometries and Good Energies
D5.4.3 The Minimization Treatment
D5.4.4 How Does Minimization Works?
D5.4.5 Minimization Methods
D5.4.6 Many Variables Are Minimized
D5.4.7 Minimization is a Time-Consuming Treatment
D5.5 Examples of Minimization
D5.5.1 Minimization with Stretching Strain
D5.5.2 Minimization with Bending Strain
D5.5.3 Minimization with Torsional Strain
D5.5.4 Minimization with Van der Waals Strain
D5.5.5 Minimization with Electrostatic Component
D5.5.6 Minimization with Hydrogen Bond Component
D5.5.7 Typical Minimization Example
D5.5.8 Distribution of Energy Strain
D5.6 Conformational Analysis in Drug Design
D5.6.1 Conformational Analysis in Drug Design
D5.6.2 Energy of the Bioactive Form
D5.6.3 Low Energy of the Bioactive Conformation
D5.6.4 Geometry of the Bioactive Conformation
D5.6.5 The Experienced Molecular Modeler
D5.6.6 Common Errors Made with Minimization
D5.6.7 Example 1 D5.6.8 Example 2
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D5.7 Molecular Dynamics
D5.7.1 Molecular Dynamics
D5.7.2 Theoretical Basis of Molecular Dynamic Calculations
D5.7.3 Local Minima and Global Minimum D5.7.4 Simulated Annealing, a Special Type of Dynamics
D5.7.5 Coherency of Molecular Motions
D5.7.6 A Typical Molecular Dynamics Run
D5.8 CHAPTER QUIZZES (Available only in Academic License)
D6. MOLECULAR GRAPHICS
D6.1 Introduction
D6.1.1 Importance of Molecular Graphics
D6.1.2 Almost Science Fiction
D6.1.3 History of Molecular Visualizations
D6.1.4 1975-1978
D6.1.5 1978-1980
D6.1.6 1980-1995
D6.1.7 1995-now
D6.1.8 Commercially Available Molecular Kits
D6.1.9 Progress in Graphical Hardware and Algorithms
D6.1.10 Algorithm 1
D6.1.11 Algorithm 2
D6.1.12 Molecular Graphics Functions
D6.2 3D Perception
D6.2.1 The Perception of the Third Dimension
D6.2.2 From 3D Coordinates to Screen Coordinates
D6.2.3 2D Projection is Not Sufficient D6.2.4 Real Time Manipulation
D6.2.5 Depth Cueing
D6.2.6 Perspective
D6.2.7 Stereo
D6.2.8 Hardware Stereo
D6.3 Visualization
D6.3.1 3D Representation of Small Molecules
D6.3.2 Line
D6.3.3 Stick
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D6.3.4 Ball & Stick
D6.3.5 CPK
D6.3.6 Quality of Rendering
D6.3.7 Atomic Color-Code Convention
D6.3.8 Coloring Molecules or Sets of Atoms D6.3.9 By Atom-type
D6.3.10 By Molecule
D6.3.11 By Color
D6.3.12 By Properties
D6.3.13 Labeling Functionalities
D6.3.14 Atom Labels
D6.3.15 Atom Numbering
D6.3.16 Proteins Representation
D6.3.17 Carbon Alpha
D6.3.18 Ribbon Representation
D6.3.19 Ribbon Types
D6.3.20 Visualization of Protein Properties
D6.4 Editing & Manipulation
D6.4.1 Structure Manipulation & Editing
D6.4.2 Add Atoms Function
D6.4.3 Delete Atoms Function
D6.4.4 Fuse Atoms Function
D6.4.5 Connect atoms Function
D6.4.6 3D Molecular Constructions D6.4.7 Real-Time Rotations, Translations and Zoom
D6.4.8 Translations
D6.4.9 Rotations
D6.4.10 Zoom
D6.4.11 Control of Torsion Angles
D6.4.12 Slab and Clip
D6.5 Surfaces & Volumes
D6.5.1 Concept and Definition of Molecular Surfaces
D6.5.2 Van der Waals
D6.5.3 Solvent
D6.5.4 Connolly
D6.5.5 Surface Types
D6.5.6 Normal
D6.5.7 Transparent
D6.5.8 Dots
D6.5.9 Visualization of Properties on Molecular Surfaces
D6.5.10 Color Coded
D6.5.11 Visualization of Properties on Molecular Surfaces
D6.5.12 The Visualization of Volumes
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D6.5.13 Mathematical Boolean Operations with Volumes
D6.6 Visualizing Interactions
D6.6.1 Visualization of Hydrogen Bonds
D6.6.2 Visualization of Molecular Bumps
D6.6.3 Surface Representations for Bump Analyses
D6.6.4 Complementary Surface Properties
D6.6.5 Electrostatic Potentials
D6.6.6 Lipophilicity Potentials
D6.6.7 Visualization of Intramolecular Interaction
D6.6.8 Schematic Complex Interaction
D6.6.9 Visualization of a Complex Cavity
D6.6.10 Overview of the Entire Complex
D6.6.11 Results of Quantum Mechanical Calculations
D6.7 CHAPTER QUIZZES (Available only in Academic License)
D7. SELECTED EXAMPLES IN 3D ANALYSIS
D7.1 Conformational Analysis
D7.1.1 Ethane D7.1.2 n-Butane
D7.1.3 1-Butene
D7.1.4 Butadiene
D7.1.5 Amide
D7.1.6 Cyclohexane
D7.2 Conjugated Systems
D7.2.1 Butadiene
D7.2.2 Pentenone
D7.2.3 Dipyrrole
D7.2.4 Biphenyl
D7.2.5 Atropisomerism of Biphenyls
D7.2.6 Binaphthyl
D7.3 Aromatic Systems
D7.3.1 Planarity of Polyaromatic Systems
D7.3.2 Distorted Naphthalene
D7.3.3 Annelated Polyaromatic Benzenes
D7.3.4 Fusing Another Ring D7.3.5 Fusing Again Another Ring
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D7.3.6 Continue to Fuse Additional Rings
D7.4 Cyclic Systems
D7.4.1 Why Substituents Prefer to be Equatorial?
D7.4.2 Mono-Substituted Cyclohexanes
D7.4.3 t-Bu
D7.4.4 Phenyl
D7.4.5 Methyl
D7.4.6 Hydroxy
D7.4.7 Example of Preferred Axial Conformer
D7.4.8 Di-Methyl-1,2-Cyclohexane
D7.4.9 Trans
D7.4.10 Cis
D7.4.11 Di-Methyl-1,3-Cyclohexane
D7.4.12 Trans D7.4.13 Cis
D7.4.14 Di-Methyl-1,4-Cyclohexane
D7.4.15 Trans
D7.4.16 Cis
D7.4.17 Trans 1,3-Di-t-Butyl-Cyclohexane
D7.4.18 Chloro-2 Cyclohexanone
D7.5 Other Systems
D7.5.1 Decalins
D7.5.2 Cis-decalin
D7.5.3 Methyl-Cis-decalin
D7.5.4 Trans-decalin
D7.5.5 Interactions of Aromatic Rings
D7.5.6 Interactions Revealed by X-Ray Crystallography
D7.5.7 Two Major Types of Aromatic Interactions
D7.5.8 Overview of Possible Interactions
D7.5.9 Geometry of Ester Groups
D7.5.10 Cyclic Ester
D7.5.11 Geometry of Amide Groups
D7.5.12 Substituted Amide
D7.5.13 Cyclic Amide
E. GENERAL TOPICS
E1. GENERAL INTRODUCTION TO DRUGS
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E1.1 What is a Drug
E1.1.1 What is a Drug?
E1.1.2 Improvement of Life Expectancy
E1.1.3 Origin of Active Principles E1.1.4 Drug Formulation
E1.1.5 Multiple Names of Drugs
E1.1.6 Example of Multiple Names of a Drug
E1.1.7 Requirements for the Ideal Drug
E1.1.8 Safety
E1.1.9 Properties
E1.1.10 Compliance
E1.1.11 Pharmacology
E1.1.12 Metabolism and ADME
E1.1.13 Side Effects and Toxicity
E1.2 The Pharmaceutical Industry
E1.2.1 Drug Discovery and Development, a Long Process
E1.2.2 Drug Discovery and Drug Development
E1.2.3 One Million Studied for One to Reach the Market
E1.2.4 Pharmaceutical R&D, a High-Risk Undertaking
E1.2.5 The Time of Developing a New Drug
E1.2.6 The Cost of Developing a New Drug
E1.2.7 Reasons for Termination of Development
E1.3 Industry Focus Area
E1.3.1 Industry Focus Areas and Examples of Useful Drugs
E1.3.2 Cardiovascular System (CVS)
E1.3.3 Antiarrhytmics
E1.3.4 Antihypertensive
E1.3.5 Vasodilatation
E1.3.6 Anticoagulants
E1.3.7 Antihyperlipidemic
E1.3.8 Anti-infective Agents
E1.3.9 Antibiotics
E1.3.10 Antiviral
E1.3.11 Antifungals
E1.3.12 Antimalarias
E1.3.13 Antituberculosis
E1.3.14 Central Nervous System (CNS) Agents
E1.3.15 Antipsychotics
E1.3.16 Cholinergic
E1.3.17 Parkinsonians
E1.3.18 Anticonvulsants
E1.3.19 Antidepressants
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E1.3.20 Tranquilizers
E1.3.21 Adrenergic
E1.3.22 Gastro-Intestinal Drugs
E1.3.23 Antidiarrhea
E1.3.24 Laxatives E1.3.25 Anti-emetics
E1.3.26 Anti-Ulcers
E1.3.27 Anti-Neoplastic (Anti Cancer) Agents
E1.3.28 Alkylating
E1.3.29 Antimetabolites
E1.3.30 Anti-neoplastic
E1.3.31 Immunosuppressants
E1.3.32 Taxoids
E1.3.33 Respiratory Agents
E1.3.34 Bronchodilators
E1.3.35 Antihistamines
E1.3.36 Antitussives
E1.3.37 Anti-Rheumatism and Pain Agents
E1.3.38 Anti-inflammatory
E1.3.39 Anti-rheumatism
E1.3.40 Analgesics
E1.3.41 Anesthetics
E1.3.42 Agents Against Metabolic Disorders
E1.3.43 Antidiabetic
E1.3.44 Antiosteoporotic
E1.3.45 Thyroid Hormone
E1.3.46 Steroids
E1.3.47 Diagnostic Agents
E1.4 CHAPTER QUIZZES (Available only in Academic License)
E2. DRUG DISCOVERY
E2.1 Introduction
E2.1.1 Drug Discovery
E2.1.2 Target Identification
E2.1.3 Lead Discovery
E2.1.4 Lead Optimization
E2.1.5 Disciplines Involved in Drug Discovery
E2.2 Discovery Methods
E2.2.1 How Are Leads Discovered?
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E2.3 Serendipity
E2.3.1 The Serendipitous Pathway
E2.3.2 Penicillin
E2.3.3 Aspirin E2.3.4 Glafenine
E2.3.5 Furosemide
E2.3.6 Chlorpromazine
E2.3.7 Cyclosporin A
E2.3.8 Viagra
E2.4 Screening
E2.4.1 The Screening Pathway
E2.4.2 Example of Molecules Discovered by Screening
E2.5 Chemical Modification
E2.5.1 The Chemical Modification Pathway
E2.5.2 Tagamet
E2.5.3 Beta-Blockers
E2.5.4 Limitation of the Chemical Modification Approach
E2.6 Rational Drug Design
E2.6.1 The Rational Pathway
E2.6.2 Captopril Story E2.6.3 Cimetidine Story
E2.6.4 The Histamine Action
E2.6.5 Screening Molecules Related to Histamine
E2.6.6 The Guanidine Analog
E2.6.7 The Burimamide Lead
E2.6.8 The Metiamide Molecule
E2.6.9 The Cimetidine Drug
E2.6.10 The Ranitidine Drug
E2.6.11 Advantages of Rational Drug Design
E2.7 Chemistry in Drug Discovery
E2.7.1 Chemistry in Drug Discovery
E2.7.2 Synthesis of Complicated Molecules
E2.7.3 Penicillin
E2.7.4 Taxol
E2.7.5 Steroid
E2.7.6 Three Methods in Synthetic Chemistry
E2.7.7 Classical
E2.7.8 Parallel
E2.7.9 Combinatorial
E2.7.10 Chemistry in Lead Discovery
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E2.7.11 Protein Kinase Example
E2.7.12 Chemistry in Lead Optimization
E2.7.13 Optimization of the Gleevec Series
E2.7.14 CCK-A Receptor Antagonist Example
E2.7.15 Chemistry in Drug Development
E2.8 Patents
E2.8.1 Intellectual Property and Patents
E2.8.2 What Can be Patented?
E2.8.3 Requirements for Patentability
E2.8.4 Lifetime of a Patent
E2.8.5 Effective Patent Lifetime
E2.8.6 Patent Protection
E2.9 CHAPTER QUIZZES (Available only in Academic License)
E3. DRUG DEVELOPMENT
E3.1 Introduction
E3.1.1 Drug Development
E3.1.2 Pipe-Line of Development E3.1.3 Pre-Clinical Development
E3.1.4 Clinical Development
E3.1.5 Post-marketing Surveillance
E3.1.6 Disciplines Involved in Drug Development
E3.1.7 Effective Teams: Interactivity and Cooperativity
E3.2 The Pre-Clinical Studies
E3.2.1 Pre-Clinical Studies
E3.2.2 Chemical Development
E3.2.3 Pharmacological Studies
E3.2.4 Drug Metabolism and Pharmacokinetics
E3.2.5 Toxicology Studies
E3.2.6 Acute Toxicity
E3.2.7 Safety Studies
E3.2.8 Carcinogenicity
E3.2.9 Mutagenicity
E3.2.10 Reproduction Studies
E3.2.11 Formulation Development
E3.2.12 Stability Tests
E3.2.13 Disciplines Involved in Pre-Clinical Development
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E3.3 Clinical Development
E3.3.1 Introduction on Clinical Trials
E3.3.2 Clinical Trials Phase 1
E3.3.3 Clinical Trials Phase 2 E3.3.4 Clinical Trials Phase 3
E3.3.5 Clinical Trials Phase 4
E3.3.6 Disciplines Involved in Drug Development
E3.4 Regulatory Affairs
E3.4.1 The Role of the Food and Drug Administration (FDA)
E3.4.2 The Investigational New Drug Application (IND)
E3.4.3 The New Drug Application (NDA)
E3.4.4 The Regulatory Approval Process
E3.5 CHAPTER QUIZZES (Available only in Academic License)
Molecular Conceptor 2.16Synergix ltd. © 1996-2012
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