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Novel Allosteric Sites on Ras for Lead Generation 1 . 3,4 . 5 6 6 Barry J. Grant * , Suryani Lukman * , Harrison J. Hocker , Jaqueline Sayyah , Joan Heller Brown , 2,6 5 J. Andrew McCammon , Alemayehu A. Gorfe * 1 Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America, 3 Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 4 Department of Chemistry, University of Cambridge, Cambridge, United Kingdom, 5 Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, United States of America, 6 Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America 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