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

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• 作者：Andrew J. S. Knox ; Trevor Price ; Michal Pawlak ; Georgia Golfis ; Christopher T. Flood ; Darren Fayne ; D. Clive Williams ; Mary J. Meegan ; David G. Lloyd
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2177-2180
• 全文大小：213K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

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.