复旦大学：《药物化学》授课资料_Physiochemical properties in drug discovery

影响药物理化性质的因素与结构优化 Physiochemical properties in drug discovery 1. Shape Favorable Interaction 2. Plasma Protein Binding 3. Permeability 卫小文( John wai 时间:3月29日(周三)晚上18:30-20:45 地点:张江校区实验南楼325室

CONFIDENTIAL 1 1. Shape & Favorable Interaction 2. Plasma Protein Binding 3. Permeability 卫小文 (John Wai) 时间: 3月29日（周三）晚上18:30-20:45 地点: 张江校区实验南楼325室 Physiochemical properties in drug discovery 影响药物理化性质的因素与结构优化

Shape and favorable interactions Small molecules bind to protein targets through a combination of Shape complementarity (vs natural substrate/ligand Enzyme-substrate complex How to make the shape of the key fit the lock?

CONFIDENTIAL 2 Shape and favorable interactions Small molecules bind to protein targets through a combination of:

What to control molecular shapes? How to restrict conformational flexibility of inhibitors Avoidance of syn pentane/allylic 1, 3 interaction Conformational bias of common functional groups Computational conformational analysis Conformation distribution Molecular mechanic Ground state vs bound state energy

WuXiͲ Genentech MedChem Team 3 What to control molecular shapes? ¾ How to restrict conformational flexibility of inhibitors Avoidance of syn pentane/allylic 1,3 interaction ¾ Conformational bias of common functional groups ¾ Computational conformational analysis Conformation distribution: Molecular Mechanics Ground state vs bound state energy

What we learned as undergrad +09 0.9 △G°=2(.9)+1(+3.7)=5.5 kcal/mol Estimates of In-Plane 1, 2&1, 3-Dimethyl Eclipsing Interactions AG3.1

WuXiͲ Genentech MedChem Team 4 H + 0.9* + 0.9* ** What we learned as undergrad 'G

Ras farnesyl protein transferase inhibitors Ras goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation Farnesylation is necessary to attach Ras to the cell membrane for it to transfer signals from membrane receptors Lead: CAAX tetrapeptide inhibitors Growth factor receptor kinase ILK (CASPASE9 Nucleus Transcription /Proliferation

WuXiͲ Genentech MedChem Team 5 Ras farnesyl protein transferase inhibitors ¾ Ras goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Farnesylation is necessary to attach Ras to the cell membrane, for it to transfer signals from membrane receptors. Lead: CAAX tetrapeptide inhibitors

Ras farnesyl protein transferase inhibitors CAAX tetrapeptide to CAAX aminomethyl isosteres Intramolecular reaction with lactone 2N H2N Bioorganic Medicinal Chemistry, 2, 939-947, 1994

WuXiͲ Genentech MedChem Team 6 Ras farnesyl protein transferase inhibitors Bioorganic & Medicinal Chemistry, 2, 939Ͳ947, 1994 ¾ CAAX tetrapeptide to CAAX aminomethyl isosteres ¾ Intramolecular reaction with lactone H N N O H2N HS NH O OH 3

Application in Olefin Isostere Design 1992 IMe Tetrahedron Letters, 36, 3461. 1995

WuXiͲ Genentech MedChem Team 7 Application in Olefin Isostere Design Tetrahedron Letters, 36, 3461, 1995 1992

Application in Olefin Isostere Design Me-IM Me H

WuXiͲ Genentech MedChem Team 8 Application in Olefin Isostere Design

Application in Olefin Isostere Design MeMe

WuXiͲ Genentech MedChem Team 9 Application in Olefin Isostere Design

Application in Olefin Isostere Design

WuXiͲ Genentech MedChem Team 10 Application in Olefin Isostere Design