通过平滑势能面利用分子动力学计算CDK-8抑制剂的停留时间

Computing Residence Times of Cyclin-Dependent Kinase 8 Inhibitor via Potential-Scaled Molecular Dynamics Simulations

停留时间是药物研发过程中的重要参数,对筛选药物先导化合物具有重要的指导意义。但目前停留时间主要通过分子生物学实验测定,尚未有准确预测停留时间的计算化学方法。提出通过平滑势能面利用分子动力学方法来计算停留时间。在CHARMM力场下用分子动力学模拟计算了5个CDK-8抑制剂的停留时间。结果显示,停留时间的计算值大小顺序与实验测定的停留时间大小顺序一致。此方法有潜力应用于预测一般分子的停留时间,从而有助于先导化合物的筛选与合成。

Residence time is an important parameter in the process of drug research and development, and has important guiding significance for screening drug leading compounds. However, the present residence time is mainly determined by molecular biology experiments, and there is no computational chemistry method to predict residence time accurately. Here we present a methodology using potential-scalec molecular dynamics simulations to compute and predict residence time. The residence times of five Cyclin-Dependent Kinase 8(CDK-8) inhibitors are computed via potential-scaled molecular dynamics simulations. The ranking of computational residence times is in agreement with the experimental values,and this method has the potential to be used to predict the residence time of general molecules, thus lead to the screening and synthesis of lead compounds.