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Open AccessOpinion
Molecules 2018, 23(8), 1899;

Binding Affinity via Docking: Fact and Fiction

School of Pharmacy, University of Eastern Finland, P.O. BOX 1627, 70211 Kuopio, Finland
Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Strasse 14, 72076 Tübingen, Germany
Author to whom correspondence should be addressed.
Academic Editor: Rebecca Wade
Received: 4 July 2018 / Revised: 22 July 2018 / Accepted: 26 July 2018 / Published: 30 July 2018
(This article belongs to the Special Issue Molecular Modeling in Drug Design)
Full-Text   |   PDF [251 KB, uploaded 30 July 2018]


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. View Full-Text
Keywords: docking; solvent effect; binding affinity; scoring function; molecular dynamics docking; solvent effect; binding affinity; scoring function; molecular dynamics
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Pantsar, T.; Poso, A. Binding Affinity via Docking: Fact and Fiction. Molecules 2018, 23, 1899.

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