![]() In structure-based small-molecule docking a small ligand molecule is aligned inside the binding cavity of the target protein and the resulting docking pose is evaluated by a specific scoring function. Although nowadays specific docking methods are available for distinct binding partners, such as HADDOCK for protein-protein docking, here we focus on the more traditional small-molecule molecular docking methods, such as GOLD, Surflex-Dock, AutoDock and Glide, that are regularly utilized in structure-based drug design to predict ligand interactions with the target protein. Typically, these binding partners are biological macromolecules (e.g., protein, DNA/RNA, peptide) or small molecules (e.g., endogenous ligands, drugs). , is a computational method that virtually tries to predict a complex of (usually) two binding partners. We hope to provide readers with potential insights and tools to overcome the challenging issues related to binding affinity prediction via docking.ĭocking, originally introduced by Kuntz et al. 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. There are several underlying reasons for this poor performance and these are analyzed. 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. These are not the only issues that need to be considered, but they are perhaps the most critical ones. 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. The short answer is no, and this has been concluded in several comprehensive analyses. This raises the question as to whether docking is the right tool to estimate 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. 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. 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”. ![]()
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February 2023
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