Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein-Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein-Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
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DOI：
10.1021/acsomega.9b04233
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发表时间：
2020-03-10
期刊：
影响因子：
4.1
通讯作者：
Wang, Junmei
中科院分区：
文献类型：
--
作者：
He, Xibing;Liu, Shuhan;Wang, Junmei
准确预测蛋白质与配体的绝对或相对结合亲和力是计算机辅助药物设计项目的主要任务之一，特别是在导联优化阶段。原则上，炼金术自由能（AFE）方法如热力学积分（TI）或自由能摄动（FEP）可以完成这一任务，但在实践中，许多障碍阻碍了它们在日常药物设计项目中的常规应用，如计算资源要求高，计算过程缓慢，力场参数不可用或不准确，设置和后分析程序困难和不友好。在本研究中，我们利用AMBER软件包中的CPU（中央处理器）-TI和新开发的GPU（图形处理单元）-TI模块等工具，结合ff14SB/GAFF1.8力场，对蛋白质-配体结合自由能进行高效、准确的AFE计算。我们总共测试了134种蛋白质配体复合物，用于四种靶蛋白（BACE、CDK2、MCL1和PTP1B），并获得了与商业薛定谔FEP+程序相当的总体性能（Wang等）。j。化学。Soc. 2015, 137, 2695-2703)。所获得的精度符合对药物先导物优化实验工作产生有效指导的计算要求，所需的壁时间也足够短，可用于实际应用。我们的验证方案为实际药物设计项目中的常规AFE计算提供了实用的解决方案。
Accurate prediction of the absolute or relative protein-ligand binding affinity is one of the major tasks in computer-aided drug design projects, especially in the stage of lead optimization. In principle, the alchemical free energy (AFE) methods such as thermodynamic integration (TI) or free-energy perturbation (FEP) can fulfill this task, but in practice, a lot of hurdles prevent them from being routinely applied in daily drug design projects, such as the demanding computing resources, slow computing processes, unavailable or inaccurate force field parameters, and difficult and unfriendly setting up and post-analysis procedures. In this study, we have exploited practical protocols of applying the CPU (central processing unit)-TI and newly developed GPU (graphic processing unit)-TI modules and other tools in the AMBER software package, combined with ff14SB/GAFF1.8 force fields, to conduct efficient and accurate AFE calculations on protein-ligand binding free energies. We have tested 134 protein-ligand complexes in total for four target proteins (BACE, CDK2, MCL1, and PTP1B) and obtained overall comparable performance with the commercial Schrodinger FEP+ program (Wang et al. J. Am. Chem. Soc. 2015, 137, 2695-2703). The achieved accuracy fits within the requirements for computations to generate effective guidance for experimental work in drug lead optimization, and the needed wall time is short enough for practical application. Our verified protocol provides a practical solution for routine AFE calculations in real drug design projects.