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基于 3D-QSAR 和分子对接的联苯酰胺衍生物作为 p38α 丝裂原活化蛋白激酶抑制剂的研究

3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-activated protein kinase inhibitors.

机构信息

Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India.

出版信息

Mol Divers. 2012 May;16(2):377-88. doi: 10.1007/s11030-011-9353-y. Epub 2012 Jan 7.

DOI:10.1007/s11030-011-9353-y
PMID:22228035
Abstract

The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and psoriasis. Herein, we have performed 3D-QSAR and molecular docking analysis on a novel series of biphenyl amides to design potent p38 MAP kinase inhibitors. This study correlates the p38 MAP kinase inhibitory activities of 80 biphenyl amide derivatives to several stereochemical parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The resulting model from CoMFA and CoMSIA exhibited excellent [Formula: see text] values of 0.979 and 0.942, and [Formula: see text] values of 0.766 and 0.748, respectively. CoMFA predicted [Formula: see text] of 0.987 and CoMSIA predicted [Formula: see text] of 0.761 showed that the predicted values were in good agreement with experimental values. Glide (5.5) program gave the path for binding mode exploration between the inhibitors and p38α MAP kinase. We have accordingly designed novel p38α MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models.

摘要

p38α 丝裂原活化蛋白（MAP）激酶在治疗许多炎症性疾病方面发挥着重要作用，如类风湿性关节炎、炎症性肠病、克罗恩病和银屑病。在此，我们对一系列新型联苯酰胺进行了 3D-QSAR 和分子对接分析，以设计有效的 p38 MAP 激酶抑制剂。本研究将 80 种联苯酰胺衍生物的 p38 MAP 激酶抑制活性与代表立体、静电、疏水、氢键供体和受体场的几个立体化学参数相关联。CoMFA 和 CoMSIA 的结果模型表现出优异的 [Formula: see text] 值为 0.979 和 0.942，[Formula: see text] 值分别为 0.766 和 0.748。CoMFA 预测的 [Formula: see text] 值为 0.987，CoMSIA 预测的 [Formula: see text] 值为 0.761，表明预测值与实验值吻合良好。Glide（5.5）程序给出了抑制剂与 p38α MAP 激酶之间结合模式探索的途径。我们据此利用 LeapFrog 设计了新型 p38α MAP 激酶抑制剂，并在开发的模型中预测具有优异的活性。

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