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
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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
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Application in Olefin Isostere Design Me-IM Me H
WuXiͲ Genentech MedChem Team 8 Application in Olefin Isostere Design
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