Rational Drug Discovery q Full Toolbox Required to

Rational Drug Discovery q Full Toolbox Required to Compete Successfully Biological Discovery Biodisposition High Volume Screening Toxicity IND Lead Series Combinatorial Diversity Efficacy Rational [Structure, Design, Informatics] Pharmacokinetics Lead Discovery Research Iterative Process MEDC 607 & MEDC 603 Preclinical R&D 1

Rational Drug Discovery q Definition ü ü ü q Rational – Reason-based Not based on chance alone May not involve computers Types of Drug Discovery Searches ü Structure – based Drug Design (structure of the receptor, binding site, AA residues, thermodynamics) ü Pharmacophore – based Drug Design (structure of the ligand, SAR, QSAR) ü Mechanism – based Drug Design (molecular mechanism of action, transition state) MEDC 607 & MEDC 603 2

Receptor-based Drug Design q Design of Antithrombin Activators MEDC 607 & MEDC 603 3

Receptor-based Drug Design q Binding Site Information Lys 125 Arg 129 _ Lys 114 _ Arg 46 _ _ _ Asn 45 Arg 47 _ _ Arg 13 Lys 11 MEDC 607 & MEDC 603 4

Receptor-based Drug Design q -DGO (kcal/mol) Thermodynamics MEDC 607 & MEDC 603 5

Receptor-based Drug Design q Computerized Modeling MEDC 607 & MEDC 603 6

Receptor-based Drug Design q Design of New Structures A) B) 2 3 Mo. S : : R = H, R’ = OSO 3 - HINT Score ECS = (2 S, 3 S) (+)CS = (2 S, 3 R) DEF = ECS = Pentasaccharide Binding Site Residues QS : : R = OSO 3 -, R’ = H MEDC 607 & MEDC 603 7

Pharmacophore-based Drug Design q Natural Product Derivatization and Pharmacophore Elucidation Levorphanol (a morphinan) Pentazocine (Analgesic + additive) (3 – 4 X morphine analgesic + retains additive property) (less potent than morphine + reduced additive property) Methadone Meperidine Morphine R = R’ = H Codeine R = Me, R’ = H Heroin R = R’ = COCH 3 (equipotent as morphine analgesic + almost no additive) (10 -12% of morphine analgesic + much lowered additive) MEDC 607 & MEDC 603 (less potent than morphine + reduced additive property) 8

Mechanism-based Drug Design q Design of HIV Protease Inhibitor _ _ + _ _ Mechanism of Aspartic Proteinases _ _ MEDC 607 & MEDC 603 _ 9

Mechanism-based Drug Design IC 50 (n. M) Inhibitor Structure Z. Phe [CH(OH)CH 2 N]Pro. Ot. Bu HIV-1 6, 500 Z. Asn. Phe [CH(OH)CH 2 N]Pro. Ot. Bu 140 Z. Asn. Phe [CH(OH)CH 2 N]Pro. Ot. Bu 300 MEDC 607 & MEDC 603 HIV-2 330 10

Rational Design of HIV-1/2 Proteinase Inhibitors IC 50 (n. M) Inhibitor Structure HIV-1 HIV-2 Z. Leu. Asn. Phe [CH(OH)CH 2 N]Pro. Ile. NHi. Bu 750 Z. Asn. Phe [CH(OH)CH 2 N]Pro. NHi. Bu 210 Z. Asn. Phe [CH(OH)CH 2 N]PIC. NHi. Bu 18 MEDC 607 & MEDC 603 11

Rational Design of HIV-1/2 Proteinase Inhibitors IC 50 (n. M) Inhibitor Structure HIV-1 HIV-2 QC. Asn. Phe [CH(OH)CH 2 N]PIC. NHi. Bu 2 QC. Asn. Phe [CH(OH)CH 2 N]DIQ. NHi. Bu <0. 4 MEDC 607 & MEDC 603 9. 5 <0. 8 12