Drug Design

Lecture II

Mahmoud Salama , PhD

Faculty of Pharmacy
Department of Pharmaceutical Chemistry
Email: Mahmoud.salama@bue.edu.eg

Computer Aided Drug Design

Drug Discovery Before 1980

Drug Discovery After 1980

Rational Drug Design via identifying molecular target

Design of active hits based on pharmacophore
Optimization of Hit to lead compound
Prediction of binding affinity of ligands to the molecular target prior synthesis

Computer Aided Drug Design

Advantages?
Disadvantages?
Two main approaches for drug design:

Drug - Receptor Interaction

Binding Affinity: The ability of the drug to interact with the
receptor to form Drug Receptor Complex.

Drug - Receptor Interaction

Intrinsic Activity: It is the measure of the ability of the DR
complex to produce biological activity.
Agonist
Antagonist
Partial Agonist
Becketts Hypothesis

Design of Agonist
The drug must have the correct binding groups
The drug must have these binding groups correctly positioned

The drug must be the right size for the binding site
1- Binding groups

2- Binding groups Position

3- Size and Shape of the Compound

Design of Antagonist
1- Allosteric Antagonism

2- Umbrella Effect Antagonism

Drug Design Strategies

Aim: To have a better drug target interaction
There are four main methods:
Lead modification and molecular manipulation
Manual modification
Database searching
De-Novo computerized design
Targets:
To increase the activity
To reduce the side effects
To provide easy and efficient administration to the patients
To produce easily synthesized drugs

Methods of Lead Modification

Substituents Variation
Structure Extension
Chain Extension / Contraction
Ring Expansion / Contraction
Ring Variation
Structure Simplification
Structure Rigidfication
Bioisosterism
Scaffold Hopping

Substituents Variation
Alkyl Substituents:
Substitution using Methyl, Ethyl, Propyl, Butyl, Iso-propyl,
and tert-butyl
Varying the length might affect the binding affinity of the
ligands to the hydrophobic pocket

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Substituents Variation

Aryl Substituents:
Varying the substituents position affects the activity

Structure Extension

Introduction of additional functional group to increase

the binding affinity and activity

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Chain Extension / Contraction

Alteration to interatomic distance to fit the receptor

Ring Expansion / Contraction

Imipramine is tricyclic antidepressant
drug (7 membered ring).
Dimetacrine: Ring was modified to 6
membered ring to give antidepressant
effect.

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 Nevirapine: Anti HIV

Ring Variation

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Structure Simplification

Structure Rigidfication

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Isosterism
Classical Isosterism (Chemical Isosterism)
Grimms Hydride Displacement Law:

Groups that have the same number of valence electrons, but may
have a different number of atoms, are similar
Tetravalent

Trivalent

Divalent

Monovalent

CH

NH

OH

CH2

NH2

CH3
SH

Bioisosterism
Chemical groups can be related or unrelated exert the same
biological and physico-chemical properties

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Isosterism
Classical Bioisosterism

A) Classical Isosteres : by replacement of the involved atom or group by

another of the same valence
(I) Univalent Isosteres:
Example: CH3 = NH2, Cl = Br, F = OH , CH3=Cl, OH= SH

(II) Divalent Isosteres

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Isosterism
Classical Bioisosterism
(III) Ring Equivalence

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Isosterism
Classical Bioisosterism

(III) Ring Equivalence

Non-Classical Bioisosterism

They are structurally or stereo-chemically

different (of different atoms or different
arrangement of atoms) but similar in
essential parameters such as: Pka and act
on the same receptor
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Case Study I
Development of EGFR Inhibitors

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Development of EGFR Inhibitors

Staurosporine is a naturally occurring alkaloid.

Staurosprine has been known as an EGFR

competitive inhibitor, where it competes with
ATP at its binding site.

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Development of EGFR Inhibitors

Visual Representation of ATP and Staurosporine at the

receptor model
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Development of EGFR Inhibitors

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Development of EGFR Inhibitors

Visual Representation of ATP, Staurosporine, and

Pyrrolopyrimidine at the EGFR binding site
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Pharmacophore Identification
Generation of Anti-depressant drugs

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Pharmacophore Identification

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Pharmacophore Identification
Butterfly Model

Invalidation of the Butterfly MODEL

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Pharmacophore Identification
Browsing the Pharmacophore

Pharmacophore

Imipramine

Amitriptyline

Protriptyline

Assigning the Pharmacophore

RU-5031

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Pharmacophore Identification
Assigning of Pharmacophore

RU-22249

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