Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.
Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.
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DOI：
10.1021/acs.jcim.0c00613
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发表时间：
2020-11-23
影响因子：
5.6
通讯作者：
York DM
中科院分区：
文献类型：
--
作者：
Lee TS;Allen BK;Giese TJ;Guo Z;Li P;Lin C;McGee TD Jr;Pearlman DA;Radak BK;Tao Y;Tsai HC;Xu H;Sherman W;York DM
预测蛋白质-配体结合亲和力和相关的生物分子识别热力学是基于结构的药物设计的主要目标。炼金术自由能模拟为实现这一目标提供了一种高度精确和计算效率高的途径。虽然AMBER分子动力学包已经成功地在学术研究小组中用于炼金术自由能模拟数十年，但由于先前AMBER炼金术代码的限制，再加上系统设置和后处理工作流程的挑战，在工业药物发现环境中的广泛影响一直很小。通过密切的学术界和工业界合作，我们解决了许多以前的限制，旨在提高炼金术结合自由能模拟在工业药物发现应用中的准确性、效率和稳健性。在这里，我们重点介绍了AMBER20的一些最新进展，重点是炼金术结合自由能（BFE）的计算，与探索完整结合/解结合路径的替代结合自由能方法相比，它的计算强度更小。除了AMBER20的科学和技术进步之外，我们还描述了与运行相对炼金术BFE计算相关的基本实践方面，并提供了最佳实践建议，强调了炼金术模拟代码的重要性，以及获得准确可靠结果所需的辅助功能和专业知识。这项工作旨在提供与在AMBER20中运行相对BFE模拟相关的科学，技术和实际问题的当代概述，重点是现实世界的药物发现应用。
Predicting protein-ligand binding affinities and the associated thermodynamics of biomolecular recognition is a primary objective of structure-based drug design. Alchemical free energy simulations offer a highly accurate and computationally efficient route to achieving this goal. While the AMBER molecular dynamics package has successfully been used for alchemical free energy simulations in academic research groups for decades, widespread impact in industrial drug discovery settings has been minimal due to previous limitations within the AMBER alchemical code, coupled with challenges in system setup and post-processing workflows. Through a close academia-industry collaboration we have addressed many of the previous limitations with an aim to improve accuracy, efficiency and robustness of alchemical binding free energy simulations in industrial drug discovery applications. Here, we highlight some of the recent advances in AMBER20 with a focus on alchemical binding free energy (BFE) calculations, which are less computationally intensive than alternative binding free energy methods where full binding/unbinding paths are explored. In addition to scientific and technical advances in AMBER20, we also describe the essential practical aspects associated with running relative alchemical BFE calculations along with recommendations for best practices, highlighting the importance not only of the alchemical simulation code, but also the auxiliary functionalities and expertise required to obtain accurate and reliable results. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative BFE simulations in AMBER20, with a focus on real-world drug discovery applications.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
2.8
作者：
BEUTLER, TC;MARK, AE;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
影响因子：
2.9
作者：
Boresch, S;Karplus, M
通讯作者：
Karplus, M
影响因子：
2.1
作者：
Boresch, S
通讯作者：
Boresch, S
影响因子：
4.2
作者：
Bodnarchuk, Michael S.;Packer, Martin J.;Haywood, Alexe
通讯作者：
Haywood, Alexe