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Principles of Drug Design

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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Principles of Drug Design

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  1. 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

  2. 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

  3. Principles of Drug Design • Competitive Inhibition …. Example Design of Statins Substrate Inhibitor MEDC 603 Fall 2007

  4. 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

  5. + S + S E P E E I E S + P E I Principles of Drug Design • Non-Competitive Inhibition MEDC 603 Fall 2007

  6. 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

  7. 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

  8. E + S E:S Response E:I E:S:I Principles of Drug Design • Differentiation of type of inhibition MEDC 603 Fall 2007

  9. 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

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