停留时间是药物研发过程中的重要参数,在筛选药物先导化合物过程中具有重要的指导意义.目前停留时间主要通过实验测定,有成本高、速度慢的不足,而能够快速简便地准确计算停留时间的计算化学方法鲜少见.本文中提出一个通过平滑势能面利用分子动力学模拟来计算停留时间的方法.我们在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,体现了此方法的停留时间预测能力.因此方法简单易行,对计算机计算能力要求不高,经过进一步发展有潜力应用于工业上预测一般分子的停留时间,有助于筛选先导化合物,从而加速药物研发进程、降低药物研发成本.%Residence time is a key parameter during the hit-to-lead and lead optimization phases of drug discovery process. Nowadays,experimental methods to measure residence time are available but we still lack of robust computational approaches that are able to compute and predict residence time. Here we presented a methodology using potential-scaled molecular dynamics simulations to compute and predict residence time. The residence times of five Cyclin-Dependent Kinase 8 (CDK-8) inhibitors were computed via potential-scaled molecular dynamics simulations. The ranking of computational residence times is in agreement with the experimental values,which demonstrates a reasonable predictive power to estimate residence times with readily available computational resources and highlights the potential for industrial use with future exploration.
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