Discovery of novel small-molecule Src kinase inhibitors via a kinase-focused druglikeness rule and structure-based virtual screening |
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Authors: | Bian Li Lili Xu Qing Shen |
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Institution: | Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, P.R. China |
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Abstract: | Overexpression of the non-receptor tyrosine kinase Src is implicated in the development and progression of various human cancers. Blocking signalling pathways mediated by Src is believed to be a promising anticancer strategy. We report herein the discovery of novel small-molecule Src inhibitors by crystal structure-based virtual screening. A kinase-focused druglikeness rule was proposed and used in the design of compound library. Combination of large-scale docking with DOCK and rescoring with GOLD resulted in 6 hits with moderate to potent inhibitory activity against Src. Among them, compound 1 with an IC50 of 1.2 μM shows the most potent inhibitory activity. By using molecular docking, binding models of the top 3 hits (ranked by potency and ligand efficiency) with Src were constructed to provide a rational strategy that simultaneously exploits hydrogen bonding interaction in the hinge region and hydrophobic stacking in the back pocket. This approach is instructive and meaningful to further structure-based drug design of Src inhibitors. |
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Keywords: | Src kinase kinase-focused druglikeness rule structure-based virtual screening ligand efficiency |
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