Accurate Prediction of Complex Structure and Affinity for a Flexible Protein Receptor and Its Inhibitor
Accurate Prediction of Complex Structure and Affinity for a Flexible Protein Receptor and Its Inhibitor
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DOI：
10.1021/acs.jctc.6b01127
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发表时间：
2017-06-01
影响因子：
5.5
通讯作者：
Nakamura, Haruki
中科院分区：
文献类型：
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作者：
Bekker, Gert-Jan;Kamiya, Narutoshi;Nakamura, Haruki
为了准确预测柔性蛋白质受体与其抑制剂药物的结合构型以及结合亲和力，将增强采样与多正则分子动力学（McMD）模拟和热力学积分（TI）相结合作为一种通用的药物对接方法. CDK 2是细胞周期蛋白依赖性激酶2，参与细胞周期调控。CDK 2的功能异常可导致肿瘤发生，因此它是一个潜在的药物靶点。在这里，我们进行了一个长的McMD模拟对接抑制剂CS3的CDK 2从未结合的结构开始。随后，一个潜在的结合/解结合的途径，从多正则系综，结合自由能很容易地计算由TI沿着的途径。利用这种组合，获得了正确的CS3与CDK 2的结合构型，其亲和力与实验值吻合良好。
In order to predict the accurate binding configuration as well as the binding affinity for a flexible protein receptor and its inhibitor drug, enhanced sampling with multicanonical molecular dynamics (McMD) simulation and thermodynamic integration (TI) were combined as a general drug docking method. CDK2, Cyclim-dependent kinase 2, is involved in the cell cycle regulation. Malfunctions in CDK2 can cause tumorigenesis, and thus it is a potential drug target. Here, we performed a long McMD simulation for docking the inhibitor CS3 to CDK2 starting from the unbound structure. Subsequently, a potential binding/unbinding pathway was given from the multicanonical ensemble, and the binding free energy was readily computed by TI along the pathway. Using this combination, the correct binding, configuration of CS3 to CDK2 was obtained, and its affinity coincided well with the experimental value.