Structure prediction of protein–ligand complexes, called protein–ligand docking, is a critical computational technique that can be used to understand the underlying principle behind the protein functions at the atomic level and to design new molecules regulating the functions. Protein-ligand docking methods have been employed in structure-based drug discovery for hit discovery and lead optimization. One of the important technical challenges in protein–ligand docking is to account for protein conformational changes induced by ligand binding. A small change such as a single side-chain rotation upon ligand binding can hinder accurate docking. Here we report an increase in docking performance achieved by structure alignment to known complex structures. First, a fully flexible compound-to-compound alignment method CSAlign is developed by global optimization of a shape score. Next, the alignment method is combined with a docking algorithm to dock a new ligand to a target protein when a reference protein–ligand complex structure is available. This alignment-based docking method, called CSAlign-Dock, showed superior performance to ab initio docking methods in cross-docking benchmark tests. Both CSAlign and CSAlign-Dock are freely available as a web server at https://galaxy.seoklab.org/csalign.

蛋白质-配体复合物的结构预测，称为蛋白质-配体对接，是一种关键的计算技术，可用于在原子水平上理解蛋白质功能背后的基本原理，并设计调节功能的新分子。蛋白质-配体对接方法已应用于基于结构的药物发现，以实现命中发现和先导化合物优化。蛋白质-配体对接的重要技术挑战之一是解释配体结合引起的蛋白质构象变化。诸如配体结合时的单个侧链旋转之类的小变化可能会阻碍精确对接。在这里，我们报告了通过与已知复杂结构的结构对齐实现的对接性能的提高。首先，通过形状分数的全局优化开发了一种完全灵活的化合物到化合物对齐方法 CSAlign。接下来，当参考蛋白质-配体复合物结构可用时，将比对方法与对接算法相结合，将新配体与目标蛋白质对接。这种基于对齐的对接方法称为 CSAlign-Dock，在交叉对接基准测试中显示出优于从头对接方法的性能。 CSAlign 和 CSAlign-Dock 均可作为 Web 服务器免费使用，网址为 https://galaxy.seoklab.org/csalign。