Identification,Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
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| Authors: | JianMin Jia XiaoLi Xu Fang Liu XiaoKe Guo MingYe Zhang MengChen Lu LiLi Xu JinLian Wei Jia Zhu ShengLie Zhang ShengMiao Zhang HaoPeng Sun QiDong You |
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| Affiliation: | 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; 2. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.; 3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.; Wake Forest University, United States of America, |
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| Abstract: | Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization. |
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