Computer-Aided Drug Design

CADD

MB

Dr Mahmoud Bakr ١
Contents
„ What is drug design?

„ Classical Drug Design

„ Rational Drug Design

„ CADD
„ Receptor-Based Design
„ Ligand-Based Design

Dr Mahmoud Bakr ٢
Drug Design
¾ Design is a programmed search for an object.

¾ Drug Design is a terminology that covers all the

programs carried out with the purpose of
discovering new chemical substances useful in
medicine.

Dr Mahmoud Bakr ٣
 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.

Dr Mahmoud Bakr ٤
Molecular Modification of Prototype

Testing

Lead Analogues SAR

New Drug

Dr Mahmoud Bakr ٥
Strategies in Drug Design

(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.

Dr Mahmoud Bakr ٦
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 biological
property.
„ With the advances in Molecular Biology and
Computer sciences, “rational” approaches to drug
design have become more popular and important.

Dr Mahmoud Bakr ٧
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

Dr Mahmoud Bakr ٨
 Computers. What for?

„ 3D structure of a molecules is represented, visualized,

computed and interpreted.

„ It comprises:
„ Molecular Graphics
„ Computational Chemistry

„ There are many programs

Dr Mahmoud Bakr ٩
Molecular Graphics

„ Computers are used to facilitate

representation of the 3-D
structures of molecules, that can
be visualized and manipulated.

Dr Mahmoud Bakr ١٠
 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.

Dr Mahmoud Bakr ١١
 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 obtained
information.
„ Create models of molecules, models of biological
binding sites and even models of drug-receptor (D-R)
complex are provided.

Dr Mahmoud Bakr ١٢
 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

Dr Mahmoud Bakr ١٣
 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 on١٤ the
Dr Mahmoud Bakr

computer screen to explore the molecule from all angles).

 Representation of a Structure.

„ e.g. Epinephrine
„ Mol Formula C9H13NO3
OH

HO NHCH3

HO

Computer Graphic Display. How ?

Dr Mahmoud Bakr ١٥
 Computer Graphic Displays (Visualization)

„ Ball and Stick (Ball and tube)

„ Sphere and rods
„ Wire-frame
„ Space-filling
„ VdW molecular dot surface
„ Atomic charge distribution

Dr Mahmoud Bakr ١٦
3D structure of Epinephrine

OH

HO NHCH3

HO Build 3D
model

Dr Mahmoud Bakr ١٧
Different methods of visualizing Epinephrine

Dr Mahmoud Bakr Dot surface ١٨

What computers can do

Calculation of Molecular dimensions

Dr Mahmoud Bakr ١٩
Partial charges of histamine

Charge distribution on the histamine ion

Dr Mahmoud Bakr ٢٠
 What computers can do

2. Optimization of the structure

„ 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

Dr Mahmoud Bakr ٢١
 What computers can do

In computational chemistry,
major techniques are applied:

„ Quantum Mechanics: molecular orbitals

„ Spartan, MOPAC, Gaussian
„ Molecular Mechanics: energies
„ Insight / CHARM, MM2
„ Molecular Dynamics
„ Correlate motion with relaxation times
„ Explore conformation space

Dr Mahmoud Bakr ٢٢
 Molecular Dynamics

to find the most stable conformation

Dr Mahmoud Bakr ٢٣
 Molecular Dynamics

molecular dynamics to find the most stable conformation

Dr Mahmoud Bakr ٢٤
 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. Dr Mahmoud Bakr ٢٥
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.

Dr Mahmoud Bakr ٢٦
Methodology

‰ “Known” receptor ‰ “Unknown” receptor

‰ Direct DD
‰ Indirect DD
‰ Structure-based DD
‰ Ligand-based DD
‰ Macromolecular design
‰ Receptor-fit approach ‰ Small molecule design
‰ Tailor-made Drug
‰ Pharmacophore design
‰ De novo design

Dr Mahmoud Bakr ٢٧
 SBDD

„ SBDD is rational approach of DD that require

knowledge 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.

Dr Mahmoud Bakr ٢٨
 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
Dr Mahmoud Bakr ٢٩
 SBDD
„ Receptor-fit approach

„ Method aims to create molecules that can bind to structurally defined

receptor 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.

Dr Mahmoud Bakr ٣٠
 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)
Dr Mahmoud Bakr ٣١
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 can
interact 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.
Dr Mahmoud Bakr ٣٢
 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.

Dr Mahmoud Bakr ٣٣
 SBDD

2. Identification of the 3D
structure of the active site..

• Protein X-ray crystallography

• NMR spectra
• Homology modeling

Dr Mahmoud Bakr ٣٤
 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.

Dr Mahmoud Bakr ٣٥
 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.

Dr Mahmoud Bakr ٣٦
 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.

Dr Mahmoud Bakr ٣٧
 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.

Dr Mahmoud Bakr ٣٨
 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.

Dr Mahmoud Bakr ٣٩
 SBDD

8. Synthesis and biological testing:

„ Potential compounds are synthesized

„ Different biological assays are performed

Dr Mahmoud Bakr ٤٠
 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 a
satisfactory drug (potent and specific) is obtained.

Dr Mahmoud Bakr ٤١
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

Dr Mahmoud Bakr ٤٢
Structure of Methotrexate bound to Dihydrofolate
Reductase

Dr Mahmoud Bakr ٤٣
 Indinavir
Inhibitors of (HIV-1) protease.

Indinavir was designed with the help of an X-ray

crystallographic structure and molecular mechanics
calculations.

Dr Mahmoud Bakr ٤٤
DNA as a receptor

Dr Mahmoud Bakr ٤٥
 Ligand-Based Design
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 and
superimposed 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.

Dr Mahmoud Bakr ٤٦
 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

Dr Mahmoud Bakr ٤٧
 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).

Dr Mahmoud Bakr ٤٨
 CoMFA
„ 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 the
biological activity.
„ Using this 3D-QSAR technique, medicinal chemists can
predict the potency of a not-yet synthesized compound
(i.e. the hypothetical drug).
Dr Mahmoud Bakr ٤٩
 CoMFA

• Build each molecule using modelling software

• Identify the active conformation for each molecule
• Identify the pharmacophore

OH

HO NHCH3

HO
Build 3D
model
Active conformation Define pharmacophore
Dr Mahmoud Bakr ٥٠
 CoMFA

• Define fields using contour maps round a representative

molecule

Dr Mahmoud Bakr ٥١
 CoMFA Publications
„ Ablordeppey SY, El-Ashmawy MB, Glennon RA.
Analysis of the structure-activity relationships of sigma
receptor 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.

Dr Mahmoud Bakr ٥٢
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

Dr Mahmoud Bakr modeling ٥٣
CADD Software
„ Sybyl, Frodo, macromodel,

„ MM2, Discover,

„ DGeom, Disco

„ Alchemy, Chem-X, Aladdin,

„ Concord, Smile, Genie,

„ Cobra, Amber, Hint,

„ CoMFA, Catalyst, Insight

„ Dock, fit

„ Molegro
Dr Mahmoud Bakr ٥٤
 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

Dr Mahmoud Bakr ٥٥
 Quetions?

Thank U

Dr Mahmoud Bakr ٥٦