哈佛化学生物学Lecture20.pdfVIP

Chemistry 170: Chemical Biology Lecture 20 Harvard University Fall 2003 Professor David Liu Rational Design of Macromolecular Ligands (Part 2: Proteins) • Approaches to drug development • HIV and HIV protease – Development of Saquinavir – Development of Ritanovir – Cyclic ureas: a new approach – Resistance to protease inhibitors • Principles of structure-based drug design The Pharmaceutical Industry • 2002 pharmaceutical industry: $424,000,000,000 ( GDP of all but 12 countries) – $1 billion = recombinant vaccines – $2 billion = therapeutic antibodies – $14.5 billion = non-Ig proteins (1999 figures) • 94% = $282,500,000,000 = small molecule drugs • 2003: average cost to develop a drug = ~$900 M The Challenge of Drug Development • The vast majority of drug candidates that show promising in vitro (or even in vivo) properties fail to make it to market – Poor chemical potency (dissociation constant of the protein-drug complex) – Poor biostability (suitability as an enzyme substrate; ability to be hydrolyzed) – Poor bioavailability (size, polarity, solubility, # of rotatable bonds) – Poor toxicology (specificity of binding, immunogenicity) – Not cost effective (too many steps; materials or purification too expensive) – Not marketable (inability to enter the body orally, unpopular side effects) • Two common approaches to drug development: 1. Random screening and structure-activity relationships drive structural modification, done either in traditional or high-throughput for