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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

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slide1

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

MEDC 603 Fall 2007

slide2

kCAT

E + S E:S P + E

KM

KI

I

E:I

Principles of Drug Design

  • Competitive Inhibition

+

+

S

S

E

P

E

E

I

E

I

MEDC 603 Fall 2007

slide3

Principles of Drug Design

  • Competitive Inhibition …. Example

Design of Statins

Substrate Inhibitor

MEDC 603 Fall 2007

slide4

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.

MEDC 603 Fall 2007

slide5

+

S

+

S

E

P

E

E

I

E

S

+

P

E

I

Principles of Drug Design

  • Non-Competitive Inhibition

MEDC 603 Fall 2007

slide6

Exosite II

Thrombin

Active Site

Exosite I

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

MEDC 603 Fall 2007

slide7

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.

MEDC 603 Fall 2007

slide8

E + S E:S Response

E:I

E:S:I

Principles of Drug Design

  • Differentiation of type of inhibition

MEDC 603 Fall 2007

slide9

E + S E:S E-S No further rxn.

Principles of Drug Design

  • Irreversible Inhibition

Substrate behaves as an inhibitor!

aka …. Suicide substrate inhibitors or Mouse trap inhibitors or Trojan horse inhibitors

MEDC 603 Fall 2007