Biochemistry Sixth Edition Bonus Chapter: Drug Development Copyright © 2005 by W. H. Freeman and Company Berg Tymoczko Stryer

Know “ADME” Administration - Absorption Distribution in the body Metabolism - Transformation Excretion

Lipinski’s Rules MW should be less than 500 H-bond donors less than 5 H-bond acceptors less than 10 Partition coefficient less than 5 Otherwise drug will have poor absorption!

From HW, mol wt = 604

Know structures of conjugates Glutathione (ECG) via -SH Glucuronides from UDP-Glucuronic Sulfate from PAPS (A-stick 3’P, 5’PS)

Serendipity Drugs discovered accidentally

Screening Compare activities of large libraries of drugs. SAR structure activity relationships

Cholesterol Lowering Drugs Statins found by screening

Drug design for known target Becoming more important. Once a drug is known, variants can be screened for activity. Some HIV protease inhibitors:

Co-crystal structure of Arachidonic acid (ball and stick) and Cox-1. The TYR and ARG stabilize the carboxylic acid. The ILE and the Aromatic Wall hem the Arachidonic acid into the binding site. ARG ILE TYR SER Aromatic Wall Arachidonic Acid

ARG ILE TYR SER Aromatic Wall Model of Aspirin (ball-and-stick) and Cox-1. The SER residue on the enzyme has attacked the aspirin, hydrolyzing the acetyl group and irreversibly inactivating the enzyme. Acetyl Group Salicylic Acid

Practical Guide to Identifying Non-Selective vs Selective Cox Inhibitors it appears that most non-selective Cox inhibitors share the following linear arrangement of functional groups: GreasyArylAlkylAcidic Indomethacin Ibuprofen Ketoprofen Etodolac Med chemists can use this SAR to guide the development of newer, better (hopefully) non- selective Cox inhibitors.

Practical Guide to Identifying Non-Selective vs Selective Cox Inhibitors Most Cox-2 selective inhibitors are shaped like an arrowhead: Greasy Side chain (usually sulfonamide or sulfonyl) Aryl Polar The SAR for non-selective Cox inhibitors is clearly different from Cox-2 selective inhibitors. Med chemists can exploit this fact to design novel compounds. rofecoxibvaldecoxib Like celecoxib, except Br is Me group etoricoxib

Analyzing Genomic Information Known targets (Protein Kinases or 7TM receptors = GPCR) can suggest new drugs.

Model Animals also yield targets Knockout mice tell us about interesting genes/proteins