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Molecular Conceptor - Table of Contents
Practical Drug Discovery: Case StudiesLast updated on September 2012
A - DRUG DISCOVERY
1. Case Studies in SAR Analyses
2. Success Stories in Drug Discovery
B - ANALOG DESIGN AND MOLECULAR MIMICRY
1. Case Studies in Advanced Analog Design
2. Case Studies in 3D Mimic Design
3. Case Studies in Peptidomimetics
C - SYNTHESIS AND LIBRARY DESIGN
1. Case Studies in Library Design
D - ADME PROPERTIES AND PREDICTIONS
1. Case Studies in ADME/Tox Predictions
E - STRUCTURE-BASED DESIGN
1. Case Studies in Structure-Based Design
2. Case Studies of Docking in Drug Discovery
F - CHEMINFORMATICS
1. Case Studies in 3D Database Searching
G - LIGAND-BASED DESIGN
1. Case Studies in Ligand-Based Design
H - QSAR AND CHEMOMETRICS
1. Case Studies in QSAR and 3D-QSAR
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A. DRUG DISCOVERY
A1. CASE STUDIES IN SAR ANALYSES
A1.1 Case Study-1 : Banyu Example
A1.1.1 The Banyu Story with the Urea Structure
A1.1.2 Importance of the Entire Urea Moiety
A1.1.3 Bioactive Conformation?
A1.1.4 Design of Compounds with a Cis Conformation
A1.1.5 Good Exploitation of the SAR Analyses
A1.2 Case Study-2 : Dioxobenzothiazole Example
A1.2.1 The Dioxobenzothiazole Scaffold
A1.2.2 Optimization of the Dioxobenzothiazole Lead
A1.2.3 SAR Analyses
A1.2.4 Docking of the Dioxobenzothiazole Molecule
A1.2.5 Being Trapped with a Bad Scaffold
A1.3 Case Study-3 : EGF-R Kinase Inhibitors
A1.3.1 Therapeutic Utility of EGF-R Kinase Inhibitors
A1.3.2 Amino-4 Quinazoline Inhibitors: Iressa and Tarceva
A1.3.3 Analysis of Tarceva Binding to the EGF-R Kinase (1/4)
A1.3.4 Analysis of Tarceva Binding to the EGF-R Kinase (2/4)
A1.3.5 Analysis of Tarceva Binding to the EGF-R Kinase (3/4)
A1.3.6 Analysis of Tarceva Binding to the EGF-R Kinase (4/4)
A1.3.7 SAR of the Quinazoline Scaffold
A1.3.8 SAR of Fused Rings in the Quinazoline Scaffold
A1.3.9 Analysis of a Surprising Observation
A1.3.10 Analysis of Atomic Charges in the Different Analogs
A1.3.11 Optimal Binding of Inhibitor 17
A1.4 Case Study-4 : Nifedipine Example
A1.4.1 Two Inactive Analogs of Nifedipine
A1.4.2 Analysis of the 4' Substituted Analogs of Nifedipine
A1.4.3 Analysis of the 4 Substituted Analogs of Nifedipine
A1.4.4 Molecular Geometry of Phenyl-4 Dihydropyridine
A1.4.5 Preferred Conformation of Nifedipine
A1.4.6 Preferred Conformation of Methyl-4 Nifedipine
A1.4.7 Bioactive Conformation of Nifedipine-Like Antagonists A1.4.8 SAR Analyses Require Great Attention
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A1.7 Case Study-7 : Anilino-Quinazoline Example
A1.7.1 Potent Inhibitor of the EGF-R Protein Kinase
A1.7.2 SAR: Substitution of Anilino N4
A1.7.3 N-Methyl Analog A1.7.4 SAR Observations in a 4-Anilino-Quinazolines Series
A1.7.5 Conformation of 4-Anilino-Quinazoline Molecules
A1.7.6 Geometry of 4-Anilino-Quinazoline Structures
A1.7.7 Experimental Conformations of Anilino-Quinazolines
A1.7.8 SAR: Substitution of N4 is Detrimental to Potency
A1.7.9 Torsion Angle N3-C4-N4-C1' is Important for Potency
A1.7.10 Energy of Bioactive Conformers
A1.7.11 Browser of Selected Anilino-Quinazoline Analogs
A1.7.12 Docking of 4-Anilino-Quinazoline Lead
A1.7.13 Summary of Structural Analyses
A1.8 ADDITIONAL CASE STUDIES
A1.8.1 Additional Case Studies
A2. SUCCESS STORIES IN DRUG DISCOVERY
A2.1 Success Story-1 : Captopril
A2.1.1 Captopril
A2.1.2 Captopril Target - ACE
A2.1.3 Starting Point: Venom Causes Drop in Blood Pressure
A2.1.4 Snake Venom Acts on the ACE Cascade
A2.1.5 The Captopril Story
A2.1.6 Developing an Assay for ACE
A2.1.7 Isolating and Purifying the Venom Peptides
A2.1.8 Encouraging Clinical Trial Results
A2.1.9 Project Virtually Abandoned at Squibb
A2.1.10 Back to the Project
A2.1.11 Applying the Concepts to ACE
A2.1.12 The Basis of ACE and CPA Similarity
A2.1.13 X-ray Structure of CPA
A2.1.14 Modeling the Active Site of ACE (1/4)
A2.1.15 Modeling the Active Site of ACE (2/4)
A2.1.16 Modeling the Active Site of ACE (3/4)
A2.1.17 Modeling the Active Site of ACE (4/4)
A2.1.18 Design of a Novel ACE Inhibitor
A2.1.19 The Phe-Ala-Pro Pharmacophore
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A2.1.20 Finding a Lead Compound
A2.1.21 The Discovery of Captopril
A2.1.22 The Captopril Project Timeline
A2.1.23 What Made the Success of the Project Possible?
A2.1.24 Structure-Based Component A2.1.25 Ligand-Based Component
A2.1.26 Following the Discovery
A2.1.27 Recent Structure of Captopril-ACE Complex
A2.1.28 Other Drugs in This Class
A2.2 Success Story-2 : Aliskiren
A2.2.1 Aliskiren
A2.2.2 Aliskiren Target - Renin
A2.2.3 Starting Point
A2.2.4 The Aliskiren Story A2.2.5 The First Generation of Renin Inhibitors
A2.2.6 The Second Generation of Renin Inhibitors
A2.2.7 Peptidomimetic Approach was Unsuccessful
A2.2.8 The Need for a New Non-Peptidic Scaffold
A2.2.9 Novartis's New Rational Approach
A2.2.10 3D Model of the Enzyme
A2.2.11 Predicting the Bioactive Conformation of CGP38560
A2.2.12 The Design Strategy
A2.2.13 Finding a Feasible Scaffold
A2.2.14 Criteria for Good Candidate Molecules A2.2.15 The Parallel Design of Non-Peptide Renin Inhibitors
A2.2.16 The THQ Series
A2.2.17 Validation of the Design Strategy
A2.2.18 The Phenoxy Series
A2.2.19 Optimization of the Phenoxy Lead
A2.2.20 The Indole Series
A2.2.21 The Salicylamide Series
A2.2.22 A Docking Experiment
A2.2.23 Design of the Salicylamide Molecule
A2.2.24 Transferrable SAR's A2.2.25 Example of Transferrable SAR's
A2.2.26 Four Unrelated Lead Compounds
A2.2.27 Browser of the Novartis Renin Inhibitor Leads
A2.2.28 From Initial Lead to Aliskiren
A2.2.29 The Aliskiren Project Timeline
A2.2.30 What Made the Success of the Project Possible?
A2.2.31 The Incorporation of Modeling
A2.2.32 Modeling - The Key to Aliskiren's Success
A2.2.33 Historical Document
A2.2.34 Good Teamwork A2.2.35 Following the Discovery
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A2.2.36 X-rays of Complex with CGP38560
A2.2.37 X-ray Determination of Lead Inhibitors
A2.2.38 The Indole X-ray
A2.2.39 The S3sp sub-Pocket
A2.2.40 Other Work on Drugs in this Class
B. ANALOG DESIGN AND MOLECULAR MIMICRY
B1. CASE STUDIES IN ADVANCED ANALOG DESIGN
B1.1 Case Study-1 : Salicylanilides
B1.1.1 Salicylanilides
B1.1.2 Genistein Structure and Alignment with Quinazoline 1
B1.1.3 3D Design of a Salicylanilide Scaffold
B1.1.4 Possible Intramolecular H-Bonds in Salicylanilides
B1.1.5 Synthesis of the Molecules
B1.1.6 Biological Assays
B1.1.7 Validity of the Hypotheses
B1.1.8 Summary
B1.2 Case Study-2 : Pyrimidin-4-yl-ureas
B1.2.1 Pyrimidin-4-yl-ureas
B1.2.2 PD-166285 Reference and Novartis Design
B1.2.3 A Search in the Cambridge Structural Database
B1.2.4 Ab-Initio Calculations
B1.2.5 Synthesis of the Prototype Molecule
B1.2.6 Biological Assays for Pyrimidin-4-yl-urea
B1.2.7 Docking of Pyrimidin-4-yl-urea in c-Abl
B1.2.8 Correlation of the Activities with Size of Gate Keeper
B1.2.9 Alignment of Pyrimidin-4-yl urea and PD-166285
B1.2.10 P&G Discovered Independently the Same Molecule
B1.2.11 Optimization Towards Lck Kinase Inhibition
B1.2.12 Summary
B1.3 Case Study-3 : Anthranilamide Scaffold
B1.3.1 Anthranilamide Scaffold
B1.3.2 Structural Determinants of Anilinophtalazine Activity ?
B1.3.3 Conformational Analyses
B1.3.4 Bidentate Binding Mode Unlikely to Occur
B1.3.5 Role of the Nitrogen Phtalazine Atoms
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B1.3.6 Database Searching
B1.3.7 3D Electrostatic Potential
B1.3.8 Synthesis of the Exact Anthranilamide Mimetic
B1.3.9 Biological Tests
B1.3.10 3D Overlay of Mimic Structures B1.3.11 Determinants for Anilinophtalazine KDR/Flt-1 Activities
B1.3.12 Summary
B1.4 Case Study-4 : Phenoxyphenyltriazoles
B1.4.1 Phenoxyphenyltriazoles
B1.4.2 Requirements for Binding to the BZD Receptor
B1.4.3 Design of an Estazolam Mimic
B1.4.4 Conformational Analyses and Overlay with Diazepam
B1.4.5 Chemical Synthesis of the Mimics
B1.4.6 Confirmation of the Design Hypothesis B1.4.7 Summary
B1.5 Case Study-5 : Pro-Leu-Gly-NH2 Peptide
B1.5.1 Pro-Leu-Gly-NH2 Peptide
B1.5.2 The -Lactam Analog of Pro-Leu-Gly-NH2
B1.5.3 Design of Imidazolidinone and Diketopiperazine
B1.5.4 Biological Tests
B1.5.5 3D Alignment of Pro-Leu-Gly-NH2 and Mimics
B1.5.6 Summary
B1.6 Case Study-6 : Remoxipride Mimic
B1.6.1 Remoxipride Mimic
B1.6.2 Bioactive Conformation of Desmethylremoxipride
B1.6.3 Design of Rigid Analog
B1.6.4 Chemical Synthesis
B1.6.5 Biological Tests
B1.6.6 3D Alignments
B1.6.7 Summary
B1.7 Case Study-7 : Rimonabant Mimics
B1.7.1 Rimonabant Mimic
B1.7.2 Conformational Analysis of Rimonabant
B1.7.3 Design of Rigid Analog
B1.7.4 Chemical Synthesis
B1.7.5 Biological Tests
B1.7.6 3D Alignment of Rimonabant and Mimic
B1.7.7 Summary
B1.8 Case Study-8 : Salicylamide Mimics
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B1.8.1 Salicylamide Mimics
B1.8.2 SAR of Salicylamide 1
B1.8.3 Removing the Hydroxyl or the Carbonyl
B1.8.4 Analyzing if Ortho Electron Lone-Pair is Sufficient
B1.8.5 Potent Inhibition at Ki at Different pH B1.8.6 Pseudo-Ring of 1 Binds as a Whole Unit
B1.8.7 Design of Quinazoline Mimic
B1.8.8 3D Alignment of Salicylamide 1 and Quinazoiline 2
B1.8.9 Conclusion
B1.8.10 Summary
B1.9 Case Study-9 : Bradykinin Antagonists
B1.9.1 Bradykinin Antagonists
B1.9.2 The Problem
B1.9.3 The Stepwise Discovery of Cyclopropylamide B1.9.4 Retaining the two N-H groups
B1.9.5 Mimicking the Nitrogen Pyridine Atom by a Carbonyl
B1.9.6 Conformational Considerations
B1.9.7 First Molecules Synthesized
B1.9.8 Restoring Lipophilic Interactions
B1.9.9 Reducing Ring Size
B1.9.10 The Best Replacement
B1.9.11 Additional Factors in Cyclopropyl Replacement
B1.9.12 Torsion Angle N-C-C-N
B1.9.13 Smaller Rings have Increasing Character B1.9.14 Ring Strain and Geometry of Cyclopropyl
B1.9.15 Bulkiness of the Hydrophobic Ring
B1.9.16 3D Alignment of 1 and the Cyclopropyl Surrogate
B1.9.17 Summary
B1.9.18 Factor Xa Inhibitors
B1.9.19 Factor Xa Inhibitors with 2,3-Diaminopyridine Core
B1.9.20 Replacement May be of General Utility
B1.9.21 Surrogates Generated by Computer
B1.10 ADDITIONAL CASE STUDIES
B1.10.1 Additional Case Studies
B2. CASE STUDIES IN 3D MIMIC DESIGN
B2.1 Case Study-1 : Cimetidine Mimicry
B2.1.1 Two Very Different H2-Antagonists
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B2.1.2 Cimetidine has a Folded Conformation
B2.1.3 3D Mimicry between Cimetidine and Triazole
B2.2 Case Study-2 : Substance P Antagonists
B2.2.1 Substance P : a Ligand of CNS Receptors
B2.2.2 Conformation of Substance P
B2.2.3 Template for Mimicking the Phe-Phe Moiety
B2.2.4 The Successful Discovery of SP Antagonists
B2.2.5 A Phe-Phe Mimic of Substance P
B2.2.6 Mimicry of CGP-47899 and Substance P
B2.3 Case Study-3 : Hypolipemic Agents
B2.3.1 Reference Set of Hypolipemic Agents
B2.3.2 Design of a New Hypolipemic Agent
B2.3.3 RU 25961 is a 3D Mimic of Treloxinate
B2.3.4 Browser of Hypolipemic Agents
B2.3.5 Methyl Treloxinate
B2.3.6 Biological Activities of Cis and Trans Isomers
B2.3.7 Browser of Hypolipemic Agents
B2.4 Case Study-4 : Polymerase-1 Inhibitors
B2.4.1 Therapeutic utility of PARP-1 Inhibitors
B2.4.2 3-Amino Benzamide PARP-1 Inhibitor
B2.4.3 Design with Carboxamide Geometry Locked B2.4.4 3D Mimicry between Structure C and NU-1085
B2.4.5 Synthesis of the Designed Tricyclic Compounds
B2.4.6 Validation of the Concept by X-Ray Crystallography
B2.4.7 Browser of PARP-1 Inhibitors
B2.5 Case Study-5 : Angiotensin-II Antagonists
B2.5.1 Antagonists of Angiotensin-II Receptors
B2.5.2 Losartan as a Mimic of Angiotensin-II (1/5)
B2.5.3 Losartan as a Mimic of Angiotensin-II (2/5)
B2.5.4 Losartan as a Mimic of Angiotensin-II (3/5)
B2.5.5 Losartan as a Mimic of Angiotensin-II (4/5)
B2.5.6 Losartan as a Mimic of Angiotensin-II (5/5)
B2.5.7 Browser of Angiotensin-II Antagonists
B2.6 Case Study-6 : Cholecystokinin Receptor Ligands
B2.6.1 Design of Cholecystokinin Receptor Ligands
B2.6.2 Pharmacophore Analysis: CCK-A Antagonists (1/3)
B2.6.3 Pharmacophore Analysis: CCK-A Antagonists (2/3)
B2.6.4 Pharmacophore Analysis: CCK-A Antagonists (3/3)
B2.6.5 Design of a New Lorglumide Analog
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B2.7 Case Study-7 : Farnesyltransferase Inhibitors
B2.7.1 Farnesyltransferase, a Target in Oncology
B2.7.2 X-ray Structure of FTase with a Tetrapeptide
B2.7.3 Binding Interactions of CAAX Substrate for FTase B2.7.4 4-Aminobenzoic Spacer to Replace Val-Ile Dipeptide
B2.7.5 Superposition with X-Ray Structure of Initial Tripeptide
B2.7.6 The Simple Aromatic Central Ring is not Sufficient
B2.7.7 Analogs with Significantly Enhanced Potency
B2.7.8 3D Mimicry of FTI-276 and Reference Tetrapeptide
B2.7.9 Docking of FTI-276 and Reference Tetrapeptide
B2.7.10 Terphenyl to Replace the Central Val-Ile Dipeptide
B2.7.11 Alignment of FTI-289 with Cys-Val-Ile-Met
B2.7.12 Potent and Selective Farnesyltransferase Inhibitor
B2.7.13 X-ray of Abbott-21 bound to Farnesyltransferase
B2.7.14 Browser of Farnesyltransferase Inhibitors
B2.8 Case Study-8 : Antagonists of the Mdm2-p53 Interaction
B2.8.1 Antagonists of the Mdm2-p53 Interaction
B2.8.2 Mdm2 Bound to p53 Transactivation Domain (1/4)
B2.8.3 Mdm2 Bound to p53 Transactivation Domain (2/4)
B2.8.4 Mdm2 Bound to p53 Transactivation Domain (3/4)
B2.8.5 Mdm2 Bound to p53 Transactivation Domain (4/4)
B2.8.6 Systematic SAR Studies
B2.8.7 Contribution of the Amino-Acids to the Binding B2.8.8 3D Structure of the Pharmacophore
B2.8.9 The Novartis 5 nM Peptide-Like Antagonist
B2.8.10 Peptide 2 Designed to Stabilize Helical Conformations
B2.8.11 Peptide 3 Designed for a Salt Bridge with a Tyrosine
B2.8.12 Filling Empty Space Identified by Modeling
B2.8.13 Problems with the Peptide-Based Antagonists
B2.8.14 The Bicyclo [2.2.1]-Heptane Scaffold
B2.8.15 Designed Scaffold Aligned with the Pharmacophore
B2.9 ADDITIONAL CASE STUDIES
B2.9.1 Additional Case Studies
B3. CASE STUDIES IN PEPTIDOMIMETICS
B3.1 Case Study-1 : Somatostatin Mimicry
B3.1.1 Somatostatin Structure
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B3.1.2 Somatostatin Receptors
B3.1.3 Subtypes of Somatostatin Receptors
B3.1.4 The Drug Discovery Strategy
B3.1.5 The Somatostatin Pharmacophore
B3.1.6 Successful Reduction of the Somatostatin B3.1.7 Mimics of L-363,377 with Database Searching
B3.1.8 Results of the Database Searching
B3.1.9 A Good Mimic of the Reference Cyclic Peptide
B3.1.10 Development of a Combinatorial Chemistry Approach
B3.1.11 Combinatorial Chemistry Results
B3.1.12 An Integrated Approach to Drug Discovery
B3.2 Case Study-2 : -Opioid Receptor Agonists
B3.2.1 Therapeutic utility of-Opioid Receptor Agonists
B3.2.2 Typical Peptide -Opioid Receptor Agonists B3.2.3 Typical Non-Peptide -Opioid Receptor Agonists
B3.2.4 Pharmacophore for -Opioid Receptor Agonists
B3.2.5 SAR, NMR and Modeling of the DPDPE series (1/3)
B3.2.6 SAR, NMR and Modeling of the DPDPE series (2/3)
B3.2.7 SAR, NMR and Modeling of the DPDPE series (3/3)
B3.2.8 Bioactive Conformation of DPDPE (1/4)
B3.2.9 Bioactive Conformation of DPDPE (2/4)
B3.2.10 Bioactive Conformation of DPDPE (3/4)
B3.2.11 Bioactive Conformation of DPDPE (4/4)
B3.2.12 Scaffold Design of Non-Peptide Antagonists B3.2.13 Refinement of the Scaffold and Substituents
B3.2.14 Amino Group not Included
B3.2.15 Reducing the Number of Chiral Centers
B3.2.16 Substituent with Variable Hydrophobicity
B3.2.17 The First Series Synthesized
B3.2.18 The (-) SL-3111 Enantiomer
B3.3 Case Study-3 : MC4R Melanocortin Receptor Agonists
B3.3.1 Melanocortin Receptors
B3.3.2 Minimal Peptide Sequence for Activating the Receptor
B3.3.3 Strategy for the Design of New Agonists
B3.3.4 Cyclic Peptide 1
B3.3.5 Molecular Geometry of the Cyclic Peptide
B3.3.6 Design of Molecules with a Cyclohexane Core
B3.3.7 Acyl Groups to Keep the Compound Neutral
B3.3.8 Cis and Trans Cyclohexane Isomers
B3.3.9 Cis Isomer
B3.3.10 Trans Isomer
B3.3.11 Geometry of Cis Isomer with Tryptamine Equatorial
B3.3.12 Geometry of Cis Isomer with Tryptamine Axial
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B3.3.13 Geometry of Trans Isomer: Substituents Equatorial
B3.3.14 Cis Isomer Equatorial Aligned with Peptidic Agonist
B3.3.15 Cis Isomer Axial Aligned with Peptidic Agonist
B3.3.16 Trans Isomer Aligned with Peptidic Agonist
B3.3.17 Discovery of a Nanomolar Non-Peptidic Agonist B3.3.18 A Good Starting Point for Further Developments
B3.4 Case Study-4 : Renin Inhibitors
B3.4.1 The Renin-Angiotensin System Cascade
B3.4.2 The First Generation of Renin Inhibitors
B3.4.3 Example of Inhibitor
B3.4.4 The Second Generation of Renin Inhibitors
B3.4.5 Low Oral Absorption of CGP-38560
B3.4.6 Bioactive Conformation of CGP-38560
B3.4.7 Analysis of the Predicted Bioactive Conformation B3.4.8 Strategy for the Design of Non-Peptidic Inhibitors
B3.4.9 Successful Design of a Non-Peptidic Inhibitor
B3.4.10 Optimization of the Tetrahydroquinoline Inhibitor
B3.4.11 A Third Generation of Renin Inhibitors
B3.4.12 Alignment of the Non-Peptide Inhibitors in 3D
B3.5 Case Study-5 : Inhibitors of HLE
B3.5.1 Inhibition of Human Leukocyte Elastase
B3.5.2 Problem of Peptide-Based ICI-200,880
B3.5.3 TFMK as a Reference
B3.5.4 Analysis of the Binding of TFMK (1/4)
B3.5.5 Analysis of the Binding of TFMK (2/4)
B3.5.6 Analysis of the Binding of TFMK (3/4)
B3.5.7 Analysis of the Binding of TFMK (4/4)
B3.5.8 Summary of the Analyses
B3.5.9 Design of a New Pyridone Framework
B3.5.10 3D Superimposition with TFMK
B3.5.11 Synthesis of Pyridone Molecule
B3.5.12 3D Geometry Maintained after Removal of Proline
B3.5.13 Analysis of the Pyridone Bound to PPE
B3.5.14 Optimization of the Pyridone Series
B3.5.15 Browser of HLE Inhibitors
B3.6 ADDITIONAL CASE STUDIES
B3.6.1 Additional Case Studies
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C. SYNTHESIS AND LIBRARY DESIGN
C1. CASE STUDIES IN LIBRARY DESIGN
C1.1 Case Study-1 : CDK2 Inhibitors
C1.1.1 Purine Scaffold as a Source of Bioactive Molecules
C1.1.2 CDK2 Biological Target and Known Inhibitors
C1.1.3 Diverse 2,6,9-trisubstituted Purine Libraries
C1.1.4 Substituent Design
C1.1.5 Additivity of the Biological Effects
C1.1.6 Browser of Substituents at the C-2 Position
C1.1.7 Browser of Substituents at the C-6 Position
C1.1.8 Successive Rounds
C1.1.9 Library Results
C1.2 Case Study-2 : DHFR Inhibitors
C1.2.1 Diaminopyrimidines DHFR Inhibitors
C1.2.2 Soluble Diaminopyrimidine Scaffold
C1.2.3 Design of 2,4-Diaminopyrimidine Library
C1.2.4 Structure-Based Design Strategy
C1.2.5 3D Structural Data Available
C1.2.6 2,4-Diaminopyrimidine Anchorage to DHFR
C1.2.7 Docking of the Virtual Library
C1.2.8 Selection and Synthesis
C1.2.9 Biological Tests
C1.2.10 Detailed Analysis of Binding Mode
C1.2.11 Enantiomers with Different Activities
C1.2.12 Binding Mode and Absolute Stereochemistry
C1.2.13 Diversity-Based Strategy
C1.2.14 Selection Based on Diversity of Pair Overlaps
C1.2.15 Selection of Molecules and Biological Tests
C1.2.16 Structure-Based vs. Diversity-Based Strategy
C1.2.17 Efficiency of the Structure-Based Selection
C1.2.18 Summary
C1.2.19 What can we Learn from this Study ?
C1.3 Case Study-3 : Aminothiazole Libraries
C1.3.1 Design of Diverse and Focused Libraries
C1.3.2 Steps in Library Design Process
C1.3.3 Define Chemical Reaction
C1.3.4 Select Pool of Possible Building Blocks
C1.3.5 Refine List of Building Blocks
C1.3.6 Library Enumeration C1.3.7 Reaction-Based Enumeration
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C1.3.8 Fragment-Based Enumeration
C1.3.9 Properties Profiling of the Virtual Library
C1.3.10 Simple Property Profiling
C1.3.11 Profiling of Knowledge-Based Properties
C1.3.12 Analysis of the Diversity of the Virtual Library C1.3.13 Optimal Subset of the Virtual Library for Synthesis
C1.3.14 Frequency Analysis Method
C1.3.15 Advanced Frequency Analysis
C1.3.16 Example of Advanced Frequency Analysis
C1.3.17 Multicriteria Optimization
C1.3.18 The Weighted Sum Approach
C1.3.19 Limitation of the Weighted Sum Approach
C1.3.20 Multiple Objective Genetic Algorithms (MOGA)
C1.3.21 MOGA Plot and Pareto Ranking
C1.3.22 Example of Multi-Dimensional Optimization
C1.3.23 MOGA Results
C1.3.24 Expanding one MOGA Solution
C1.4 ADDITIONAL CASE STUDIES
C1.4.1 Additional Case Studies
D. ADME PROPERTIES AND PREDICTIONS
D1. CASE STUDIES IN ADME/TOX PREDICTIONS
D1.1 ADME/Tox Case Study 1: Identification of Non-Genotoxic Carcinogens
D1.1.1 Identification of Non-Genotoxic Carcinogens
D1.1.2 Current ADME/Tox Analyses
D1.1.3 Possible Models for Non-Genotoxic Carcinogens
D1.1.4 Both Receptors Form Heterodimers
D1.1.5 Activation for the Arylhydrocarbon Receptor
D1.1.6 The Responsive Elements of Interaction (1/2)
D1.1.7 The Responsive Elements of Interaction (2/2)
D1.1.8 Binding Analysis of the Arylhydrocarbon Receptor (AhR)
D1.1.9 Ligand Identification of the Arylhydrocarbon Receptor (AhR)
D1.1.10 Induction on the mRNA Level by AhR
D1.1.11 Induction on the Enzyme Level by AhR
D1.1.12 Similar Induction of Enzyme Activity Between Species (1/2)
D1.1.13 Similar Induction of Enzyme Activity Between Species (2/2)
D1.1.14 Examples of Rat Specific Induction of Enzyme Activities D1.1.15 Examples of Human Specific Induction of Enzyme Activities
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D1.1.16 Conclusion
D1.1.17 Outcome of this Testing
D1.2 ADME/Tox Case Study 2: Interpretation of Toxicology from an ADMETStandpoint
D1.2.1 Case Studies Presented Here
D1.2.2 The Action of a Drug
D1.2.3 Reasons for Species Specific Responses
D1.2.4 Example-1: Differences in Metabolism
D1.2.5 Different Metabolism of the two Analogs
D1.2.6 Ketoconazole Binding
D1.2.7 Desacetyl-Ketoconazole Binding
D1.2.8 Example-2: Differences in Rate of Metabolism
D1.2.9 PK /PD Model of Response
D1.2.10 Origin of the Hepatotoxicity of Procicromil in Dog D1.2.11 Toxicity due to Different Plasma Clearance Values
D1.2.12 Example-3: Differences in Receptor Affinity
D1.2.13 Affinity for Cardiac Na+/K+ ATPase (1/2)
D1.2.14 Affinity for Cardiac Na+/K+ ATPase (2/2)
D1.2.15 Interpretation of Toxicology from Animal Data
D1.2.16 Interpretation of Toxicology from Human Data
D1.3 ADME/Tox Case Study 3: Drug Withdrawals due to Toxicity
D1.3.1 Drug Failures, Lessons and Learnings for the Future
D1.3.2 Three Types of Drug Withdrawals
D1.3.3 Type A
D1.3.4 Type B
D1.3.5 Type C
D1.3.6 Type D
D1.3.7 Table of Drug Withdrawals from 1980
D1.3.8 Type A1 Drug Withdrawals
D1.3.9 Alosetron
D1.3.10 Cerivastatin
D1.3.11 Flosequinan
D1.3.12 Encainide
D1.3.13 Rofecoxib
D1.3.14 Lessons from Withdrawals due to Primary Pharmacology
D1.3.15 A Broad Spectrum of Drugs
D1.3.16 Impact on Decisions in Drug Discovery
D1.3.17 Type A2 Drug Withdrawals
D1.3.18 Fenfluramine and Dexfenfluramine (1/2)
D1.3.19 Fenfluramine and Dexfenfluramine (2/2)
D1.3.20 Rapacuronium
D1.3.21 Astemizole, Cisapride, Grepafloxacin and Terfenadine (1/2)
D1.3.22 Astemizole, Cisapride, Grepafloxacin and Terfenadine (2/2)
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D1.3.23 Mibefradil
D1.3.24 Lessons from Withdrawals Due to Secondary Pharmacology
D1.3.25 Impact on Discovery Screening Programs
D1.3.26 Type B and C Toxicity Drug Withdrawals (1/4)
D1.3.27 Type B and C Toxicity Drug Withdrawals (2/4) D1.3.28 Type B and C Toxicity Drug Withdrawals (3/4)
D1.3.29 Type B and C Toxicity Drug Withdrawals (4/4)
D1.3.30 Lessons Learned from Type B/C Toxicity
D1.3.31 Importance of Dose in B and C Toxicity
D1.3.32 Type D Toxicity Drug Withdrawals
D1.3.33 Thalidomide
D1.3.34 Balancing Benefit / Risk
D1.3.35 Benefit Analyses for Antidepressants
D1.3.36 Monitoring
E. STRUCTURE-BASED DESIGN
E1. CASE STUDIES IN STRUCTURE-BASED DESIGN
E1.1 Case Study-1 : Phenyl Imidazoles
E1.1.1 Phenyl-Imidazoles Inhibit Cytochrome P450
E1.1.2 Simple Consideration: Shape Similarity
E1.1.3 Perhaps Binding Elements are more Complex ?
E1.1.4 The Structure-Based Answer
E1.1.5 Phenyl-Imidazole Browser
E1.1.6 Limitations of Chemical Intuition
E1.2 Case Study-2 : BACE-1 Inhibitors
E1.2.1 BACE-1 Inhibitors
E1.2.2 Screening the J&J Corporate Compound Collection
E1.2.3 Structural Determinants of the Biological Activity of 1
E1.2.4 X-ray Structure of the Complex of 1 with BACE-1
E1.2.5 Flap Flexibility in Aspartyl Proteases
E1.2.6 Compound with Increased Folding Capability
E1.2.7 How to Gain Additional Binding
E1.2.8 Design of a More Potent Inhibitor
E1.2.9 X-Ray Structure of the Complex with 3a
E1.2.10 Pharmacological Action of Compound 3a
E1.2.11 Important Structural Determinants for Binding
E1.2.12 Summary
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E1.3 Case Study-3 : Factor Xa Inhibitors
E1.3.1 Therapeutic Utility of Factor Xa Inhibitors
E1.3.2 DX-9065a : a Factor Xa Inhibitor
E1.3.3 Complex Between Factor Xa and DX-9065a E1.3.4 Analysis of the Factor Xa and DX-9065a Complex (1/4)
E1.3.5 Analysis of the Factor Xa and DX-9065a Complex (2/4)
E1.3.6 Analysis of the Factor Xa and DX-9065a Complex (3/4)
E1.3.7 Analysis of the Factor Xa and DX-9065a Complex (4/4)
E1.3.8 Role of the Carboxylic Acid in Selectivity (1/3)
E1.3.9 Role of the Carboxylic Acid in Selectivity (2/3)
E1.3.10 Role of the Carboxylic Acid in Selectivity (3/3)
E1.3.11 Initial Inhibitor Design
E1.3.12 Design (step 1): Structural Moiety for Pocket S1
E1.3.13 Phenyl-Amidine Entered into the S1 Pocket
E1.3.14 Phenyl-Amidine Oriented in Lowest Energy Orientation
E1.3.15 Design (step 2): Structural Moiety for Pocket S4
E1.3.16 Phenyl Ring Introduced in Pocket S4
E1.3.17 Phenyl Substituted with an Amidine
E1.3.18 Stacking Interaction of Phenyl-Amidine with Trp-215
E1.3.19 Phenyl-Amidine Orientation
E1.3.20 Design (step 3): Design of the Spacer
E1.3.21 Phenyl-Amidine Groups in their Preferred Orientations
E1.3.22 Spacer with three Atoms
E1.3.23 Candidate Prototype in the Catalytic Site
E1.3.24 Design (step 4): Positioning of the Carboxylate
E1.3.25 Discovery of a Lead Compound
E1.3.26 Optimization of the Designed Series
E1.3.27 Interaction of Compound 21 with Factor Xa
E1.3.28 Finding an Optimal Spacer
E1.4 Case Study-4 : Kinase Inhibitors
E1.4.1 Pyrrolo-Pyrimidine & Quinazoline EGF-R Inhibitors
E1.4.2 Novartis and Parke-Davis Opposite Binding Models
E1.4.3 Controversy: Novartis & Parke-Davis Binding Modes E1.4.4 Parke-Davis Analyses
E1.4.5 Novartis Analyses
E1.4.6 X-ray Structure of ATP Bound to a Kinase
E1.4.7 Binding Mode of ATP
E1.4.8 Binding Mode of Staurosporine
E1.4.9 Homology Model of EGF-R Catalytic Site
E1.4.10 From Staurosporine to Pyrrolo-pyrimidine
E1.4.11 The Novartis Binding Mode of Pyrrolo-pyrimidine
E1.4.12 The Pyrrole Ring in the Large Pocket
E1.4.13 The Pyrrole Ring Pointing Towards the Sugar Pocket E1.4.14 Parke-Davis Analyses the Quinazoline Scaffold
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E1.4.15 Additional SAR Analyses made by Parke-Davis
E1.4.16 Parke-Davis Model of the Quinazoline Analogs
E1.4.17 Specificity Observed in EGF-R Kinase Inhibition
E1.4.18 Anilino Towards the Sugar Pocket not Reasonable
E1.4.19 Parke-Davis Model Consistent with Observed SAR E1.4.20 Binding Mode of the Pyrrolo-Pyrimidine Series
E1.4.21 Binding Mode of the Quinazoline Series
E1.4.22 What is the Correct Solution?
E1.4.23 Ligand Observed with a Novartis Binding Mode
E1.4.24 Alignment with the Novartis Model
E1.4.25 Ligand Observed with a Parke-Davis Binding Mode
E1.4.26 Alignment with the Parke-Davis Model
E1.4.27 X-Ray Resolution of Tarceva Bound to EGF-R Kinase
E1.4.28 Conclusion
E1.5 ADDITIONAL CASE STUDIES
E1.5.1 Additional Case Studies
E2. CASE STUDIES OF DOCKING IN DRUG DISCOVERY
E2.1 Case Study 1 : Pyrimidin-4-yl-ureas for Kinase Inhibition
E2.1.1 Inhibitor Active on Several Protein Kinases
E2.1.2 Structural Determinants for the Activity
E2.1.3 Correlation with the Volume of Gate Keeper Residue
E2.1.4 Outcome of this Study
E2.2 Case Study 2 : Inhibition of CHK1
E2.2.1 The CHK1 Kinase
E2.2.2 The Indazole Series
E2.2.3 Binding Mode of the Indazole Core E2.2.4 Binding Modes of the Potent Indazole Analog
E2.2.5 Pocket may Help for Selectivity
E2.2.6 Overlay with Other Chk1 Inhibitors
E2.2.7 Structure-Based Screening of Chk1 Inhibitors
E2.2.8 Hits Identified by Virtual Screening
E2.2.9 X-Ray Structures of Four Virtual Screening Hits
E2.2.10 Binding Modes Predicted for Other Five Hits
E2.2.11 Outcome of this Study
E2.3 Case Study 3 : Thrombin Inhibitors
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E2.3.1 Two Methods of Virtual Screening
E2.3.2 Combining Structure-Based and Ligand-Based VS
E2.3.3 Screening Protocol
E2.3.4 Steps of the Docking Treatment
E2.3.5 Specificity Pockets in Thrombin E2.3.6 Development of the Hybrid Approach
E2.3.7 Inhibition Assays of Top-Scoring Compounds
E2.3.8 Analysis of the Binding Mode of Compound 1
E2.3.9 Binding Mode Compared with Known Inhibitors
E2.3.10 What was Learned in this Test Study ?
E2.3.11 Analyzing Top Ranked Compounds
E2.3.12 Limitations of Scoring Functions
E2.4 Case Study 4 : Salicylamide Renin Inhibitor
E2.4.1 Search for New Scaffold in Renin Inhibition E2.4.2 3D Analyses
E2.4.3 Preferred Location of Phenyl Ring in Pocket P3
E2.4.4 Docking Experiment
E2.4.5 Results of the Docking
E2.4.6 Search for an Optimal Spacer
E2.4.7 The Salicylamide Lead
E2.4.8 Predictions Confirmed by X-Ray Study
E2.4.9 Browser of Salicylamide Inhibitor
E2.4.10 Optimization of the Salicylamide Series
E2.4.11 Summary E2.4.12 Lead Hopping
E2.5 Case Study 5 : Inhibition of Human Neutrophil Elastase
E2.5.1 Inhibition of Human Neutrophil Elastase
E2.5.2 Sesquiterpene Lactones
E2.5.3 Studies on 17 Sesquiterpene Lactones
E2.5.4 Docking Studies
E2.5.5 Docking Protocol
E2.5.6 Results of the Docking Studies
E2.5.7 Elucidation of the Mode of Action
E2.5.8 Docking Results of Melampolides 2 and 4
E2.5.9 Docking Results of Podachaenin 14
E2.5.10 Docking Results of Germacranolide 8
E2.5.11 Structural Determinants for Binding to HNE
E2.5.12 Summary
E2.6 ADDITIONAL CASE STUDIES
E2.6.1 Additional Case Studies
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F. CHEMINFORMATICS
F1. CASE STUDIES IN 3D DATABASE SEARCHING
F1.1 Case Study-1 : Ligands of the Dopamine D3 Receptor
F1.1.1 Reference Compounds
F1.1.2 Pharmacophore Model
F1.1.3 Model of the Dopamine D3 Receptor
F1.1.4 Residues Involved in the Binding
F1.1.5 Combined Pharmacophore and Structure-Based Searching
F1.1.6 Results of the 3D Searching
F1.1.7 Summary
F1.1.8 Browser of Dopamine D3 Receptor Ligands
F1.2 Case Study-2 : Non-Peptidic Cyclophilin Ligands
F1.2.1 Reference Compound: Cyclosporin A
F1.2.2 The Bioactive Conformation of Cyclosporin A
F1.2.3 Pharmacophore Model
F1.2.4 Results of 3D Searching
F1.2.5 Superposition of the Hit with Cyclosporin-A
F1.2.6 Optimization of Initial Hit F1.2.7 Browser of Non-Peptidic Cyclophilin Ligands
F1.3 Case Study-3 : Motilin Receptor Antagonists
F1.3.1 Motilin Receptor Antagonists
F1.3.2 Motilin Receptor and Motilin Peptide
F1.3.3 Structural Analyses on Motilin
F1.3.4 Analyses of Motilin Folding
F1.3.5 Bioactive Conformation of Motilin
F1.3.6 Biologically Relevant Residues of Motilin
F1.3.7 The Motilin Pharmacophore
F1.3.8 RWJ-64583: a Trisubstituted Cyclopentene Lead
F1.3.9 The Three-point Pharmacophore and RWJ-64583
F1.3.10 Optimization of the Initial Lead Molecule
F1.3.11 Mimicking the Phe-5 of Motilin
F1.4 Case Study-4 : Inhibitors of HIV-1 Protease
F1.4.1 HIV-1 Protease Inhibition
F1.4.2 The Peptide Problem
F1.4.3 Database Searching for Non-Peptidic Scaffolds
F1.4.4 The Terphenyl Derivative Hit
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F1.4.5 Analysis of the Content of the Hit
F1.4.6 Replacing Cyclohexanone by a 7-Membered Ring
F1.4.7 Problem of the 6-membered Ring
F1.4.8 Optimal Framework: 7-membered Cyclic Urea
F1.4.9 Design of Cyclic Urea Scaffold F1.4.10 XK-263 is a Non-Peptidic Mimic of A-77003
F1.4.11 Summary
F1.5 Case Study-5 : Non-Sugar Antagonists of Selectin
F1.5.1 Reference Compound
F1.5.2 Initial SAR Analyses
F1.5.3 Pharmacophore Model
F1.5.4 Results of 3D Searching
F1.5.5 Optimization of the Diphenyl Ether Hit
F1.5.6 Optimization of the Diphenyl Ether Hit F1.5.7 Optimization of the Diphenyl Ether Hit
F1.5.8 Summary
F1.5.9 Browser of Selectin Antagonists
F1.6 Case Study-6 : Dopamine Transporter Inhibitors
F1.6.1 The Dopamine Transporter Target
F1.6.2 Methodology: 3D Database Searching
F1.6.3 First Pharmacophore
F1.6.4 3D Searching Results with the First Pharmacophore
F1.6.5 Piperidinol Hit
F1.6.6 Optimization of the Piperidinol Hit
F1.6.7 Quinuclidine Hit
F1.6.8 Optimization of the Quinuclidine Hit
F1.6.9 Phenyl-4 Piperidine Hit
F1.6.10 Optimization of the Phenyl-4 Piperidine Hit
F1.6.11 Challenging the First Pharmacophore
F1.6.12 Structural Analyses of the Quinuclidine Hit
F1.6.13 Modeling Analyses: C=O Not Necessary!
F1.6.14 Browser Associated to the First Pharmacophore
F1.6.15 What Can Be Learned So Far?
F1.6.16 Second Pharmacophore
F1.6.17 Characteristics of the Second Pharmacophore
F1.6.18 3D Searching with the Second Pharmacophore
F1.6.19 Optimization of the Pyrrolidine Hit
F1.6.20 What Can Be Learned So Far?
F1.6.21 Browser Associated to the Second Pharmacophore
F1.6.22 Third Pharmacophore
F1.6.23 Bioactive Form of Mazindol
F1.6.24 Characteristics of the Third Pharmacophore
F1.6.25 3D Searching with Third Pharmacophore
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F1.6.26 Browser Associated to the Third Pharmacophore
F1.6.27 Fourth Pharmacophore
F1.6.28 Aligning Low Energy Conformers
F1.6.29 Characteristics of the Fourth Pharmacophore
F1.6.30 3D Searching with the Fourth Pharmacophore F1.6.31 Optimization of the Substituted Pyridine Hit
F1.6.32 Browser Associated to the Fourth Pharmacophore
F1.6.33 Summary
F1.7 ADDITIONAL CASE STUDIES
F1.7.1 Additional Case Studies
G. LIGAND-BASED DESIGN
G1. CASE STUDIES IN LIGAND-BASED DESIGN
G1.1 Case Study-1 : Aromatase Inhibitors
G1.1.1 Therapeutic Utility of Aromatase Inhibitors
G1.1.2 Reference Set of Aromatase Inhibitors
G1.1.3 Pharmacophore for Aromatase Inhibitors (1/3)
G1.1.4 Pharmacophore for Aromatase Inhibitors (2/3)
G1.1.5 Pharmacophore for Aromatase Inhibitors (3/3)
G1.1.6 The Design of a New Inhibitor of Aromatase
G1.1.7 Browser of Aromatase Inhibitors
G1.2 Case Study-2 : Substance P Antagonists
G1.2.1 Therapeutic Utility of Substance P Antagonists
G1.2.2 Reference Set of Substance P Antagonists
G1.2.3 Pharmacophore for Substance P Antagonists
G1.2.4 Origin of the Poor Activity of SP4
G1.2.5 Constrained Boat Conformation of CP96345
G1.2.6 The Design of a Potent Substance P Antagonist
G1.2.7 The Superimposition of CP96345 and CP99994
G1.2.8 Browser of Substance P Antagonists
G1.3 Case Study-3 : Tricyclic Antidepressants
G1.3.1 Mode of Action of Tricyclic Antidepressants
G1.3.2 Reference Set of Antidepressant Molecules
G1.3.3 Invalidation of the "Butterfly" Model G1.3.4 Pharmacophore for Antidepressants
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G1.3.5 Browser for Antidepressant Agents
G1.3.6 The Design of RU-22249
G1.3.7 Browser for Antidepressant Agents
G1.4 Case Study-4 : Morphinan Analgesics
G1.4.1 Importance of Energies in Ligand-Based Design
G1.4.2 Morphinan and D-nor Morphinan Alignment
G1.4.3 Conformational Analysis of Morphinan
G1.4.4 Conformational Analysis of D-nor Morphinan
G1.4.5 A Rationale for Explaining the Activities Observed
G1.4.6 Morphinan: Validation and Design
G1.4.7 Preferred Conformer of Active Enantiomer
G1.4.8 Preferred Conformer of Inactive Enantiomer
G1.4.9 Restoring Activities to the Inactive Analog?
G1.4.10 Morphinan Browser G1.4.11 What We Can Learn From The Morphinan Example
G1.5 ADDITIONAL CASE STUDIES
G1.5.1 Additional Case Studies
H. QSAR AND CHEMOMETRICS
H1. CASE STUDIES IN QSAR AND 3D-QSAR
H1.1 Case Study-1 : QSAR of Capsaicin Analogs
H1.1.1 Example of Capsaicin Analogs
H1.1.2 Relevant Descriptors of Capsaicin Analogs
H1.1.3 The Capsaicin Study Table
H1.1.4 Graphical Analysis of Capsaicin Analogs
H1.1.5 Deriving a QSAR Linear Equation
H1.1.6 Experimental vs. Calculated Values (1/2)
H1.1.7 Experimental vs. Calculated Values (2/2)
H1.1.8 Calculating r for the Capsaicin analogs
H1.1.9 t-test for the Capsaicin Analogs
H1.1.10 F-test for a Series of the Capsaicin Analogs
H1.1.11 The QSAR Equation for the Capsaicin Analogs
H1.1.12 Predicting the Activities of Unknown Compounds
H1.2 Case Study-2 : 3D-QSAR of Steroid Analogs
H1.2.1 The Reference Compounds
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H1.2.2 The Biological Data
H1.2.3 Molecular Alignment
H1.2.4 CoMFA Field Calculations
H1.2.5 CoMFA and PLS Results vs. Classical QSAR
H1.2.6 Steric CoMFA Map for Binding to TBG H1.2.7 Electrostatic CoMFA Map for Binding to TBG
H1.2.8 CBG Affinities of New Steroids
H1.2.9 Predicting the CBG Affinities of New Steroids
Molecular Conceptor 2.16Synergix ltd. 1996-2012