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Dr Mahmoud Bakr ١
Computer-Aided Drug Design
CADD
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Dr Mahmoud Bakr ٢
ContentsContents
What is drug design?
Classical Drug Design
Rational Drug Design
CADD
Receptor-Based Design
Ligand-Based Design
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Dr Mahmoud Bakr ٣
Drug Design
Design is a programmed search for an object.
Drug Design is a terminology that covers all the
programs carried out with the purpose of
discovering new chemical substances useful in
medicine.
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Dr Mahmoud Bakr ٤
Strategies in Drug Design
(1) Classical DD
Molecular Modification of lead
The oldest
Arising from the progress in Organic Chemistry in the middle
of the 20th century, that made extensive chemical changes
possible.
Trial and error testing of chemical substances on animals.
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Molec u lar Modif ic a t ion o f Pro t o t ype
Lead Analogues SAR
New Drug
Testing
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(2) Rational drug design
Evolved over the past 50 years, as a result of the great
advances in computers, mathematical simulation,
statistical analysis and molecular biology.
Rational drug design (RDD) is a term that covers all the
“reasoned” approaches to develop new drugs.
It is used to indicate the logical, scientific and reasonable
processes of drug discovery.
Strategies in Drug Design
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Dr Mahmoud Bakr ٧
Rational Drug Design
The goal of the approaches is to increase the chance
of finding a useful compound.
This means that new structure can be developed with
high probability of possessing the required biologicalproperty.
With the advances in Molecular Biology and
Computer sciences, “rational” approaches to drug
design have become more popular and important.
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Computer era
In recent years, computers became
important tools in most of medicinal
chemistry laboratories.
Today’s workshop
To examine the role of computers in drug design .
CADD
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Dr Mahmoud Bakr ٩
Computers. What for?Computers. What for?
3D structure of a molecules is represented, visualized,computed and interpreted.
It comprises:
Molecular Graphics
Computational Chemistry
There are many programs
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Dr Mahmoud Bakr ١٠
Molecular Graphics
Computers are used to facilitate
representation of the 3-D
structures of molecules, that can
be visualized and manipulated.
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Dr Mahmoud Bakr ١١
Computational Chemistry
Computers can help chemists to
calculate, integrate and analyze the
properties of molecules with high
speed, precision and reliability. Collect, store, integrate, view and
manipulate data.
Computers can calculate Drug-
Receptor interactions.
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Dr Mahmoud Bakr ١٢
Molecular Modeling
Uses of Programs that can generate 3-D structures,
visualize, calculate, compute and minimize energy,
examine the conformations available to a compound,
integrate data, and manipulate all the obtainedinformation.
Create models of molecules, models of biological
binding sites and even models of drug-receptor (D-R)
complex are provided.
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What is a Model?What is a Model?
At its simplest, a molecular model consists of
a series of atoms in 3D space, and their
connectivity.
Hand-held Models
Computer Graphic model
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What Computers can do
1. Representation of molecules
Generation of 3-D of small molecules (drugs and candidates) from
two-dimensional formulae.
Label atoms and stereochemistry
Generation of 3D structures of large molecules (receptors or enzymes)
Definition of the bond distances & bond angles within molecules.
Generation of all conformers.
Representation of the space-filling models, VdW, electronic charge
distribution, ……
Manipulation of structures (by allowing rotation of all models on the
computer screen to explore the molecule from all angles).
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Representation of a Structure.Representation of a Structure.
e.g. Epinephrine
Mol Formula C9H13NO3
Computer Graphic Display. How ?
NHCH3
OH
HO
HO
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Computer Graphic Displays (Visualization)Computer Graphic Displays (Visualization)
Ball and Stick (Ball and tube)
Sphere and rods Wire-frame
Space-filling
VdW molecular dot surface
Atomic charge distribution
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3D structure of Epinephrine
NHCH3
OH
HO
HO Build 3DBuild 3D
modelmodel
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Different methods of visualizing Epinephrine
Dot surface
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Calculation of Molecular dimensions
What computers can do
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Partial charges of histamine
Charge distribution on the histamine ion
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What computers can do
Generation of all conformers of the small molecules.
Calculation of the energy (conformational)
Representation of 3-D structure of optimized molecule (i.e.
molecule with minimal energy)
Estimation of all molecular and physico-chemical properties.
Calculation of conformational energy of macromolecules
2. Optimization of the structure
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What computers can do
Quantum Mechanics: molecular orbitals
Spartan, MOPAC, Gaussian
Molecular Mechanics: energies
Insight / CHARM, MM2
Molecular Dynamics Correlate motion with relaxation times
Explore conformation space
In computational chemistry,
major techniques are applied:
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Molecular Dynamics
to find the most stable conformation
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Molecular Dynamics
molecular dynamics to find the most stable conformation
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What computers can do
3. Development of models
Development of models (optimized structures) of both small
molecules (Drugs or candidates) and macromolecules
(enzymes or receptor sites).
Allow binding of small molecules to macromolecules .
Calculate energy of interaction. The lowest possible energy
reflects the highest stability of the complex and hence, the
highest fitting pattern between drug and macromolecule.
Comparison of designed complexes
Analysis of data.
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What computers can do
4. Final goals
Prediction of the biological activity of
“theoretical” molecules.
Design of new drugs: modified or from scratch
“de novo”
Identification of the Pharmacophore
Mapping of receptor sites.
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MethodologyMethodology
“Known” receptor
Direct DD
Structure-based DD
Macromolecular design
Receptor-fit approach
Tailor-made Drug
De novo design
“Unknown” receptor
Indirect DD
Ligand-based DD
Small molecule design
Pharmacophore design
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SBDD
SBDD is rational approach of DD that requireknowledge of the 3D structure of the biological target is
known. (receptor, enzyme, ..)
The structure of a new drug is designed on the basis of
its fit with the 3D receptor site structure.
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Great Advances
Advances in molecular biology and protein chemistry provided pure
protein in quantities to allow structural studies of enzymes & receptors.
Modern techniques: NMR and X-ray crystallography, are used to
picture the receptor or enzyme topography, to ascertain how D-R or
substrate-enzyme interaction may take place and which forces may be
involved.
Advances in Computer software and hardware to allow the display and
manipulation of 3D models of drug molecules and Protein structures.
PDB
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SBDD
Receptor-fit approach
Method aims to create molecules that can bind to structurally definedreceptor or inhibit structurally known enzymes (i.e. a tailor-made
drug).
Look and Key theory (Is it Glove and Hand?)
The suggested molecule is manipulated and allowed to fit in the
receptor cavity.
The models of the complex (D-R complex) are further refined by
theoretical calculation.
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SBDD
With the structure of the target protein-ligand
complex, one can:
Understand the SAR of existing compounds in a better way
Improve the lead optimization process
Suggest new analogues to be synthesized in a current series,
…….. … and …
Develop novel concepts and ideas for completely new ligand
moieties unrelated to that of known ligands. i.e. new lead
generation. (de novo design)
d d i
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de novo design
Techniques to propose new ligands that are
complementary to the active site.
These use 3D searching of large databases (library
search) to identify small molecule fragments that caninteract with specific sites in the receptor, bridging
fragments with the correct size and geometry, or
framework structures which can support functional
groups at favorable orientations.
Such tools are available in Cerius2.
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Methodology in SBDD
1. Selecting (choosing) a target
depending on the therapeutic need
i.e. to define the target molecule (whether enzyme,receptor or NA) which plays a role in a physiologically-
relevant biological pathway.
The target molecule serves as the drug binding site.
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SBDD
2. Identification of the 3D
structure of the active site..
• Protein X-ray crystallography
• NMR spectra
• Homology modeling
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SBDD
3. Characterization of the active
conformation of the site
by studying and determination of the functional groups
that allow interactions with ligands
or substrates, through
the different types of bonds: Hydrogen bonding, ionic,
VdW and hydrophobic bonding.
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SBMD
4. Design of ligands (small molecules as
potential or candidate drug)
by selecting (finding or building) compounds that bind
at
the target site, through visually-assisted design, 3D-
database search or de novo design.
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SBDD
5. Docking of small molecules into binding site:
Alignment of the molecules in the active site model.
The newly designed molecules have to complement precisely the
known binding sites of the target molecule.
The selected ligand should posses the appropriate geometry to fit
into the binding site of the target molecule, with minimal steric
clashes (i.e. tight fitting).
Also, favorable interaction between the chemical groups in the
binding site and the designed compound should be achieved. i.e. the best fitting means not only complementary shapes but also
favorable energy of interaction.
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SBDD
6. Selection and design of better analogs:
The binding affinity or activity of potential
ligands is predicted.
Even the selected compounds can be further
modified.
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SBDD
7. Optimization of the identified compound:
Modifying the ligand or substrate analog to
interact more precisely with the receptor or
enzyme, and to occupy subsidiary sites,
resulting into better potency and specificity.
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SBDD
8. Synthesis and biological testing:
Potential compounds are synthesized
Different biological assays are performed
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SBDD
9. Refining the model by repeating the cycle
The new structure can be used as a basis for another
round of analysis, design, synthesis and testing.
This process can be iterated with further rounds until asatisfactory drug (potent and specific) is obtained.
SBDD l
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SBDD. examples
There are numerous programs that have been applied
successfully in the following fields:
ACE inhibitors
Hepatic HMG-CoA reductase inhibitors
Carbonic anhydrase inhibitors
DHFR inhibitors
Thymidylate synthase inhibitors
HIV protease inhibitors
Structure of Methotrexate bound to Dihydrofolate
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y
Reductase
I di i
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Indinavir
Inhibitors of (HIV-1) protease.
Indinavir
was designed with the help of an X-ray
crystallographic structure and molecular mechanics
calculations.
DNA as a receptor
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DNA as a receptor
Ligand-Based Design
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g g
Small Molecule Design
The binding macromolecule is unknown
Only a set of experimental data is available from biological
assays.
Compounds under study are energy-minimized andsuperimposed to select suitable bioactive conformation.
The design is based on the comparative analysis of the
structural features of known compounds (of active and
inactive molecules) to formulate an SAR.
S ll M l l D i
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Small Molecule Design
The Objectives
of this approach is to:
Pharmacophore mapping: to identify the Pharmacophore:
the 3-D features common to sets of active molecules are
recognized.
Receptor mapping: to map the shape and size of the
receptors site: Then, Also, the shape and electrostatic
property of the biding site are proposed.
Design of new drugs: a modified one
Ligand-Based Design: 3D-QSAR
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Ligand Based Design: 3D QSAR
In 3D-QSAR, common atoms of a set of compounds are
allowed to interact with a "hypothetical " binding site,and the energy of interaction is related to potency.
One of the most interesting contributions from
computational chemistry is a method called
Comparative Molecular Field Analysis (CoMFA ).
C MFACoMFA
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CoMFACoMFA
A combination of structural modeling (3D- and energy
calculations) and QSAR.
In this method, the steric and electrostatic properties
are represented in 3D maps and correlated with thebiological activity.
Using this 3D-QSAR technique, medicinal chemists can
predict the potency of a not-yet synthesized compound
(i.e. the hypothetical drug).
CoMFA
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Co
•
Build each molecule
using modelling software
•
Identify the active conformation for each molecule
•
Identify the pharmacophore
NHCH3
OH
HO
HO
Active conformationActive conformation
Build 3DBuild 3D
modelmodel
Define pharmacophoreDefine pharmacophore
CoMFACoMFA
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• Define fields using contour maps round a representative
molecule
CoMFA Publications
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CoMFA Publications
Ablordeppey SY, El-Ashmawy MB, Glennon RA.
Analysis of the structure-activity relationships of sigmareceptor ligands. Med. Chem. Res ., 1991, 1, 425-438.
Ablordeppey SY, El-Ashmawy MB, Fischer JB, Glennon
RA. A CoMFA investigation of sigma receptor binding
affinity: Reexamination of a spurious sigma ligand. Eur.
J. Med. Chem ., 1998, 33, 625-633.
CADD Software
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CADD Software
AutoDock Automated Docking of Flexible Ligands to
Macromolecules
Chem3D from CambridgeSoft
DOCK docking molecules
MacroModel - Molecular Modelling
MOE Molecular Operating Environment
PCMODEL small molecule modeling program
SYBYL - software from Tripos
Cerius2 and Catalyst, from Accelrys
Insight II and QUANTA for macromolecular modeling
CADD SoftwareCADD Software
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CADD SoftwareCADD Software
Sybyl, Frodo, macromodel,
MM2, Discover, DGeom, Disco
Alchemy, Chem-X, Aladdin,
Concord, Smile, Genie,
Cobra, Amber, Hint,
CoMFA, Catalyst, Insight
Dock, fit
Molegro
Uses of Computer. Summary
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Uses of Computer. Summary
Building or retrieving molecules
visualization of structures,
Changing the style (display) of structure
Energy minimization of a given conformer
Labeling the atoms and sereochemistry
Analysis of structure and properties
Superposition and Comparison
Creating models and Ligand-Macromolecule interaction
Prediction and Design
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Dr Mahmoud Bakr ٥٦
Quetions?
Thank U
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