Principles of Drug Design

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Principles of Drug Design

• Enzyme Inhibition Basics

Example 1) Statins (I) inhibit HMG CoA Reductase
(E) S HMG CoA P Mevalonate 2) I
Warfarin, E reductase, S vitamin K epoxide, P
vitamin K Other examples salicyclic acid,
physostigmine, sulfanilamide, captopril,
enalapril, finasteride,
Units of KI and IC50 M
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Principles of Drug Design

• Competitive Inhibition

S

S
E
E
E
P
I
E
I
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Principles of Drug Design

• Competitive Inhibition . Example

Design of Statins
Substrate Inhibitor
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Principles of Drug Design

• Competitive Inhibition . Example

AZT ? potent inhibitor of HIV-RT, the retroviral
polymerase which catalyzes the formation of
proviral DNA from viral RNA.
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Principles of Drug Design

• Non-Competitive Inhibition

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Principles of Drug Design

• Non-Competitive Inhibition Example

Thrombin
Thrombin
Bivalirudin
Argatroban
Competitive Non-competitive
H2N-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly
HOOC-Leu-Tyr-Glu-Glu-Pro-Ile-Glu-Glu-Phe-Asp
Bivalirudin
Argatroban
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Principles of Drug Design

• Non-Competitive Inhibition Example

Nevirapine ? potent inhibitor of HIV-RT KI nM
no resemblance to any of the natural nucleotide
substrates binds in a hydrophobic binding
pocket adjacent to the substrate-binding pocket
and modifies the rate of polymerization.
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Principles of Drug Design

• Differentiation of type of inhibition

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Principles of Drug Design

• Irreversible Inhibition

Substrate behaves as an inhibitor! aka .
Suicide substrate inhibitors or Mouse trap
inhibitors or Trojan horse inhibitors