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Dr Mahmoud Bakr ١

Computer-Aided Drug Design

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Dr Mahmoud Bakr ٢

ContentsContents

What is drug design?

Classical Drug Design

Rational Drug Design

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Receptor-Based Design

Ligand-Based Design



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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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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



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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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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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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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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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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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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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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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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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.

http://www.accelrys.com/products/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

http://www.scripps.edu/pub/olson-web/doc/autodock/

http://www.camsoft.com/

http://www.cmpharm.ucsf.edu/kuntz/dock.html

http://www.cc.columbia.edu/cu/chemistry/mmod/mmod.html

http://www.chemcomp.com/

http://www.serenasoft.com/

http://www.tripos.com/


http://www.accelrys.com/products/catalyst/

http://www.accelrys.com/products/insight/

http://www.accelrys.com/products/quanta/

http://www.accelrys.com/products/quanta/

http://www.accelrys.com/products/insight/

http://www.accelrys.com/products/catalyst/


http://www.tripos.com/

http://www.serenasoft.com/

http://www.chemcomp.com/

http://www.cc.columbia.edu/cu/chemistry/mmod/mmod.html

http://www.cmpharm.ucsf.edu/kuntz/dock.html

http://www.camsoft.com/

http://www.scripps.edu/pub/olson-web/doc/autodock/



Dr Mahmoud Bakr ٥٤

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



Dr Mahmoud Bakr ٥٦

Quetions?

Thank U

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