Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan.
Curr Top Med Chem. 2011;11(2):171-8. doi: 10.2174/156802611794863580.
Proper incorporation of protein flexibility for prediction of binding poses and affinities of small compounds has attracted increasing attention recently in computational drug design. Various approaches have been proposed to accommodate protein flexibility in the prediction of binding modes and the binding free energy of ligands in an efficient manner. In this review, the significance of incorporating protein flexibility is discussed from the structural biophysical point of view, and then various approaches of generating protein conformation ensembles, as well as their successes and limitations, are introduced and compared. Special emphasis is on how to generate a proper ensemble of conformation for a specific purpose, as well as the computational efficiency of various approaches. Different searching algorithms for the prediction of optimal binding poses of ligands, which are the core engines of docking programs, are accounted for. Scoring functions for evaluation of protein-ligand complexes are compared. Two end-point methods of free energy calculation, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Linear Interaction Energy (LIE) method, are briefly reviewed. Finally, we also provide an example for the extension of the conventional protein-ligand docking algorithm for prediction of multiple binding sites and ligand translocation pathways.
最近，在计算药物设计中，正确纳入蛋白质柔性以预测小分子化合物的结合构象和亲和力引起了越来越多的关注。已经提出了各种方法来有效地预测配体的结合模式和结合自由能，以适应蛋白质的柔性。在这篇综述中，从结构生物物理的角度讨论了纳入蛋白质柔性的重要性，然后介绍并比较了生成蛋白质构象集合的各种方法，以及它们的成功和局限性。特别强调了如何为特定目的生成适当的构象集合，以及各种方法的计算效率。还考虑了用于预测配体最佳结合构象的不同搜索算法，这些算法是对接程序的核心引擎。比较了用于评估蛋白质-配体复合物的评分函数。简要回顾了两种终点自由能计算方法，分子力学/泊松-玻尔兹曼表面区域（MM/PBSA）和线性相互作用能（LIE）方法。最后，我们还提供了一个示例，用于扩展传统的蛋白质-配体对接算法，以预测多个结合位点和配体易位途径。
