Drug Design (ELECTIVE)_Lecture 2 (2)

7/25/2019 Drug Design (ELECTIVE)_Lecture 2 (2)

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Mahmoud Salama , PhD

Faculty of PharmacyDepartment of Pharmaceutical Chemistry

Email: [email protected]

Drug Design

Lecture II
mailto:[email protected]:[email protected]


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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

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Computer Aided Drug Design

Drug Discovery Before 1980 Drug Discovery After 1980


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Advantages?

Disadvantages?

Two main approaches for drug design:

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Computer Aided Drug Design


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Drug Receptor Interaction

Binding Affinity: The ability of the drug to interact with the

receptor to form Drug Receptor Complex.


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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


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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


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Design of Antagonist

1- Allosteric Antagonism

2- Umbrella Effect Antagonism


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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


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Methods of Lead Modification

Substituents Variation Structure Extension

Chain Extension / Contraction

Ring Expansion / Contraction

Ring Variation

Structure Simplification Structure Rigidfication

Bioisosterism

Scaffold Hopping


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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

Introduction of additional functional group to increase

the binding affinity and activity

Structure Extension


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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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Ring Variation

Nevirapine: Anti HIV


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Structure Rigidfication

Structure Simplification


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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

Bioisosterism

Chemical groups can be related or unrelated exert the same

biological and physico-chemical properties

Tetravalent Trivalent Divalent Monovalent

C N O F

CH NH OH

CH2 NH2

S CH3

SH


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Isosterism

Classical Bioisosterism

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


(III) Ring Equivalence


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Isosterism


(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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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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Visual Representation of ATP and Staurosporine at the

receptor model


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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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Butterfly Model

Invalidation of the Butterfly MODEL


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Browsing the Pharmacophore

Assigning the Pharmacophore

Pharmacophore Imipramine Amitriptyline Protriptyline

RU-5031


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Assigning of Pharmacophore

RU-22249

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Drug Design (ELECTIVE)_Lecture 2 (2)