Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zürich, Switzerland.
Curr Opin Struct Biol. 2018 Feb;48:93-102. doi: 10.1016/j.sbi.2017.10.010. Epub 2017 Nov 14.
Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 10 small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics. In this review we highlight recent advancements in applications of ligand docking tools and molecular dynamics simulations to ligand identification and optimization.
近年来，计算机辅助药物设计方法发展迅速，其准确性已经达到了可以在药物发现项目中常规应用的程度。基于蛋白质结构的方法可用于预测小分子的结合模式及其相对亲和力。通过对多达 10 个小分子进行高通量对接，然后根据隐式溶剂力场进行评分，可以使用刚性蛋白质靶标可靠地识别出具有微摩尔结合能力的配体。使用显式溶剂的分子动力学是一种低通量技术，可用于描述柔性结合位点，并准确评估结合途径、动力学和热力学。在这篇综述中，我们重点介绍了配体对接工具和分子动力学模拟在配体鉴定和优化方面的最新应用进展。
