Michel Julien, Foloppe Nicolas, Essex Jonathan W
Institute of Structural and Molecular Biology, The University of Edinburgh, Edinburgh, EH9 3JR, UK.
Department of Chemistry, Yale University, New Haven, CT-06520, USA.
Mol Inform. 2010 Sep 17;29(8-9):570-8. doi: 10.1002/minf.201000051.
Structure-based drug design could benefit greatly from computational methodologies that accurately predict the binding affinity of small compounds to target biomolecules. However, the current scoring functions used to rank compounds in virtual screens by docking are not sufficiently accurate to guide reliably the design of tight binding ligands. Thus, there is strong interest in methodologies based on molecular simulations of protein-ligand complexes which are perceived to be more accurate and, with advances in computing power, amenable to routine use. This report provides an overview of the technical details necessary to understand, execute and analyze binding free energy calculations, using free energy perturbation or thermodynamic integration methods. Examples of possible applications in structure-based drug design are discussed. Current methodological limitations are highlighted as well as a number of ongoing developments to improve the scope, reliability, and practicalities of free energy calculations. These efforts are paving the way for a more common use of free energy calculations in molecular design.
基于结构的药物设计可以从能够准确预测小分子化合物与目标生物分子结合亲和力的计算方法中受益匪浅。然而，目前用于通过对接在虚拟筛选中对化合物进行排名的评分函数不够准确，无法可靠地指导紧密结合配体的设计。因此，人们对基于蛋白质-配体复合物分子模拟的方法有着浓厚的兴趣，这种方法被认为更准确，并且随着计算能力的提高，适合常规使用。本报告概述了使用自由能扰动或热力学积分方法理解、执行和分析结合自由能计算所需的技术细节。讨论了在基于结构的药物设计中可能应用的示例。强调了当前方法的局限性以及为扩大自由能计算的范围、可靠性和实用性而正在进行的一些进展。这些努力正在为自由能计算在分子设计中的更广泛应用铺平道路。
