Discovery of small molecule leads in a biotechnology datastream.
A case study of the discovery of small molecule antagonists to the integrins GPIIbIIIa (alphaII(B)beta3), alphavbeta3, LFA-1 (alphaLbeta2), alpha4beta1 and alpha4beta7 is presented from the perspective of a biotechnology research organization. A strategy incorporating protein mutagenesis and structural studies to develop a structure-activity relationship (SAR) that described the 'epitope' of the integrin ligand was crucial to the identification of peptide analogs of these proteins, and subsequently, through parallel trends in SAR, to the identification of small molecule mimetics of these peptides, which are active analogs of the protein ligands themselves.
Gadek
Thomas R
TR
Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com
McDowell
Robert S
RS
D001709:Biotechnology / Q000639:trends; D015195:Drug Design; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012106:Research / Q000639:trends
D016023:Integrins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D004364:Pharmaceutical Preparations