title: Novel allosteric sites on Ras for lead generation.
abstract: Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs.
authors: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America. bjgrant@umich.edu
authors: Barry J
authors: BJ
authors: Grant
authors: Suryani
authors: S
authors: Lukman
authors: Harrison J
authors: HJ
authors: Hocker
authors: Jaqueline
authors: J
authors: Sayyah
authors: Joan Heller
authors: JH
authors: Brown
authors: J Andrew
authors: JA
authors: McCammon
authors: Alemayehu A
authors: AA
authors: Gorfe
mesh_terms: D000495:Allosteric Site / Q000187:drug effects*; D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009711:Nucleotides; D054852:Small Molecule Libraries; D018631:ras Proteins