PHYSICAL ORGANIC ASPECTS OF MEDICINAL CHEMISTRY 5 Lectures
Dr. S. L. Cockroft
AIMS & LEARNING OUTCOMES
This course will explore the role of physical organic chemistry in understanding the relationships between the physicochemical and biological properties of pharmaceutical agents. By the end of the course you will appreciate the importance of structure/activity relationships in modern-day drug design and development. SYNOPSIS 1. Quantifying Drug-Receptor Interactions: ● van der Waals interactions ● electrostatic interactions ● the α/β hydrogen bonding scale ● solvophobic effects ● enthalpy-entropy compensation 2. Solubility & Lipophilicty: ● absolute solubility ● effects of crystal polymorphism on solubility ● partition coefficients as a measure of lipophilicity (logPo/w) ● the pH partition hypothesis ● distribution coefficients (logDo/w) ● membrane partitioning (logDmem) 3. Substituent Effects on Drug Properties: ● lipophilicity (π constants and ClogPo/w) ● pKa ● Hammett substituent constants ● hydrogen bonding ● proximity effects 4. Drug Distribution, Metabolism & Pharmacokinetics (DMPK): ● absorption ● distribution ● metabolism ● excretion ● differences based on administration route 5. Chemoinformatics in Drug Discovery & Design: ● Quantitative Structure Activity Relationships (QSAR) ● database profiling (the origin of Lipinski’s ‘Rule of 5’ for good drug likeness) ● efficient exploration of physical property space in drug screening RECOMMENDED READING ‘Modern Physical Organic Chemistry’ Eric V. Anslyn and Dennis D. Dougherty, University Science Books, 2004 ‘Quantifying Intermolecular Interactions: Guidelines for the Molecular Recognition Toolbox’ Christopher A. Hunter, Angewandte Chemie International Edition, 2004, 43, 5310-5324 ‘Pharmacokinetics and Metabolism in Drug Design’ Dennis A. Smith, Han Van De Waterbeemd, Don K. Walker, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers, Wiley-VCH Verlag GmbH, 2001