Binding Affinity via Docking: Fact and Fiction

Abstract

In 1982, Kuntz et al. published an article with the title “A Geometric Approach to Macromolecule-Ligand Interactions”, where they described a method “to explore geometrically feasible alignment of ligands and receptors of known structure”. Since then, small molecule docking has been employed as a fast way to estimate the binding pose of a given compound within a specific target protein and also to predict binding affinity. Remarkably, the first docking method suggested by Kuntz and colleagues aimed to predict binding poses but very little was specified about binding affinity. This raises the question as to whether docking is the right tool to estimate binding affinity. The short answer is no, and this has been concluded in several comprehensive analyses. However, in this opinion paper we discuss several critical aspects that need to be reconsidered before a reliable binding affinity prediction through docking is realistic. These are not the only issues that need to be considered, but they are perhaps the most critical ones. We also consider that in spite of the huge efforts to enhance scoring functions, the accuracy of binding affinity predictions is perhaps only as good as it was 10–20 years ago. There are several underlying reasons for this poor performance and these are analyzed. In particular, we focus on the role of the solvent (water), the poor description of H-bonding and the lack of the systems’ true dynamics. We hope to provide readers with potential insights and tools to overcome the challenging issues related to binding affinity prediction via docking.