1. MEDC 603 Fall 20071 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 K I and IC 50 = M

2. MEDC 603 Fall 20072 S E + S EE + P  Competitive Inhibition Principles of Drug Design E I I E + S E:S P + E E:I I KMKM k CAT KIKI

3. MEDC 603 Fall 20073 Substrate Inhibitor Design of Statins  Competitive Inhibition …. Example Principles of Drug Design

4. MEDC 603 Fall 20074  Competitive Inhibition …. Example Principles of Drug Design AZT  potent inhibitor of HIV-RT, the retroviral polymerase which catalyzes the formation of proviral DNA from viral RNA.

5. MEDC 603 Fall 20075  Non-Competitive Inhibition Principles of Drug Design S E + S EE + P E I S I E + P

6. MEDC 603 Fall 20076  Non-Competitive Inhibition … Example Principles of Drug Design Bivalirudin Thrombin Argatroban Thrombin Exosite II Exosite I Thrombin Active Site Argatroban H 2 N-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly HOOC-Leu-Tyr-Glu-Glu-Pro-Ile-Glu-Glu-Phe-Asp Bivalirudin Competitive Non-competitive

7. MEDC 603 Fall 20077 Nevirapine  potent inhibitor of HIV-RT … K I ~ 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.  Non-Competitive Inhibition … Example Principles of Drug Design

8. MEDC 603 Fall 20078  Differentiation of type of inhibition Principles of Drug Design E + S E:S Response E:I E:S:I

9. MEDC 603 Fall 20079  Irreversible Inhibition Principles of Drug Design E + S E:S E-S No further rxn. Substrate behaves as an inhibitor! aka …. Suicide substrate inhibitors or Mouse trap inhibitors or Trojan horse inhibitors