Identification of Novel Phosphodiesterase-4D Inhibitors Prescreened by Molecular Dynamics-Augmented Modeling and Validated by Bioassay
Identification of Novel Phosphodiesterase-4D Inhibitors Prescreened by Molecular Dynamics-Augmented Modeling and Validated by Bioassay
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通过分子动力学增强建模预筛选并通过生物测定验证的新型磷酸二酯酶 4D 抑制剂的鉴定
DOI：
10.1021/ci400063s
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发表时间：
2013-04-01
影响因子：
5.6
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Li, Zhe;Cai, Ying-Hong;Luo, Hai-Bin
磷酸二酯酶- 4d （PDE4D）已被证明是治疗中风的潜在靶点。在本研究中，开发并描述了一个整合药效团，分子对接，分子动力学（MD）模拟，结合自由能计算，最后与生物测定验证的过程，以从SPECS数据库中搜索新的PDE4D抑制剂。通过MD增强策略筛选的29个化合物中，15个IC50在1.9 ~ 50 μM之间（命中率为52%），6个IC50小于10 μM，这表明MD模拟可以更精确地探索pde4d抑制剂复合物的分子间相互作用，从而显著提高了筛选的命中率。本研究中描述的有效和高效的综合程序可以很容易地应用于其他药物靶点的筛选研究。
Phosphodiesterase-4D (PDE4D) has been proved to be a potential therapeutic target against strokes. In the present study, a procedure of integrating pharmacophore, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and finally validation with bioassay was developed and described to search for novel PDE4D inhibitors from the SPECS database. Among the 29 compounds selected by our MD-augmented strategy, 15 hits were found with IC50 between 1.9 and 50 μM (a hit rate of 52%) and 6 potent hits showed IC50 less than 10 μM, which suggested that MD simulations can explore the intermolecular interactions of PDE4D-inhibitor complexes more precisely and thus significantly enhanced the hit rate of this screening. The effective and efficient integrated procedures described in this study could be readily applied to screening studies toward other drug targets.