Perola Emanuele, Walters W Patrick, Charifson Paul S
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
Proteins. 2004 Aug 1;56(2):235-49. doi: 10.1002/prot.20088.
A thorough evaluation of some of the most advanced docking and scoring methods currently available is described, and guidelines for the choice of an appropriate protocol for docking and virtual screening are defined. The generation of a large and highly curated test set of pharmaceutically relevant protein-ligand complexes with known binding affinities is described, and three highly regarded docking programs (Glide, GOLD, and ICM) are evaluated on the same set with respect to their ability to reproduce crystallographic binding orientations. Glide correctly identified the crystallographic pose within 2.0 A in 61% of the cases, versus 48% for GOLD and 45% for ICM. In general Glide appears to perform most consistently with respect to diversity of binding sites and ligand flexibility, while the performance of ICM and GOLD is more binding site-dependent and it is significantly poorer when binding is predominantly driven by hydrophobic interactions. The results also show that energy minimization and reranking of the top N poses can be an effective means to overcome some of the limitations of a given docking function. The same docking programs are evaluated in conjunction with three different scoring functions for their ability to discriminate actives from inactives in virtual screening. The evaluation, performed on three different systems (HIV-1 protease, IMPDH, and p38 MAP kinase), confirms that the relative performance of different docking and scoring methods is to some extent binding site-dependent. GlideScore appears to be an effective scoring function for database screening, with consistent performance across several types of binding sites, while ChemScore appears to be most useful in sterically demanding sites since it is more forgiving of repulsive interactions. Energy minimization of docked poses can significantly improve the enrichments in systems with sterically demanding binding sites. Overall Glide appears to be a safe general choice for docking, while the choice of the best scoring tool remains to a larger extent system-dependent and should be evaluated on a case-by-case basis.
本文描述了对当前一些最先进的对接和评分方法的全面评估，并定义了选择合适的对接和虚拟筛选方案的指导原则。文中介绍了生成一个包含大量经过高度整理且具有已知结合亲和力的药物相关蛋白质-配体复合物测试集的过程，并在同一测试集上评估了三个备受推崇的对接程序（Glide、GOLD和ICM）重现晶体学结合取向的能力。Glide在61%的情况下能在2.0 Å范围内正确识别晶体学构象，而GOLD为48%，ICM为45%。总体而言，就结合位点的多样性和配体灵活性而言，Glide的表现似乎最为一致，而ICM和GOLD的表现则更依赖于结合位点，当结合主要由疏水相互作用驱动时，其表现明显较差。结果还表明，能量最小化和对前N个构象进行重新排序可以有效克服给定对接函数的一些局限性。对相同的对接程序结合三种不同的评分函数进行了评估，以考察它们在虚拟筛选中区分活性化合物和非活性化合物的能力。在三个不同的系统（HIV-1蛋白酶、肌苷酸脱氢酶和p38丝裂原活化蛋白激酶）上进行的评估证实，不同对接和评分方法的相对性能在一定程度上依赖于结合位点。GlideScore似乎是用于数据库筛选的有效评分函数，在几种类型的结合位点上表现一致，而ChemScore在空间要求较高的位点似乎最有用，因为它对排斥相互作用的容忍度更高。对接构象的能量最小化可以显著提高在空间要求较高的结合位点的系统中的富集率。总体而言，Glide似乎是对接的一个可靠通用选择，而最佳评分工具的选择在很大程度上仍依赖于系统，应根据具体情况进行评估。
