Integration of Ligand and Structure-Based Virtual Screening for the Identification of the First Dual Targeting Agent for Heat Shock Protein 90 (Hsp90) and Tubulin
A.J.S. Knox, T. Price, M. Pawlak, G. Golfis, C.T. Flood, D. Fayne, D.C. Williams, M.J. Meegan and D.G. Lloyd, "Integration of Ligand and Structure-Based Virtual Screening for the Identification of the First Dual Targeting Agent for Heat Shock Protein 90 (Hsp90) and Tubulin", J. Med. Chem., 2009, 52 (8), pp 2177-2180
We describe the discovery of a novel indazole-based scaffold that represents the “first-in-class” dual Hsp90/tubulin binding compound. Individual known ligands for both targets shared similar 3′,4′,5′-trimethoxyphenyl cores, and from this it was hypothesized that application of an integrated ligand and structure-based virtual screening (VS) workflow could yield a single scaffold with dual binding affinity. Following validation of the VS protocol, we successfully identified a novel dual inhibitor, sourced from a commercial screening collection of 160000 compounds.
