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Binding Affinity via Docking: Fact and Fiction

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 fa...

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Autores principales: Pantsar, Tatu, Poso, Antti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222344/
https://www.ncbi.nlm.nih.gov/pubmed/30061498
http://dx.doi.org/10.3390/molecules23081899
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author Pantsar, Tatu
Poso, Antti
author_facet Pantsar, Tatu
Poso, Antti
author_sort Pantsar, Tatu
collection PubMed
description 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.
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spelling pubmed-62223442018-11-13 Binding Affinity via Docking: Fact and Fiction Pantsar, Tatu Poso, Antti Molecules Opinion 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. MDPI 2018-07-30 /pmc/articles/PMC6222344/ /pubmed/30061498 http://dx.doi.org/10.3390/molecules23081899 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Opinion
Pantsar, Tatu
Poso, Antti
Binding Affinity via Docking: Fact and Fiction
title Binding Affinity via Docking: Fact and Fiction
title_full Binding Affinity via Docking: Fact and Fiction
title_fullStr Binding Affinity via Docking: Fact and Fiction
title_full_unstemmed Binding Affinity via Docking: Fact and Fiction
title_short Binding Affinity via Docking: Fact and Fiction
title_sort binding affinity via docking: fact and fiction
topic Opinion
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222344/
https://www.ncbi.nlm.nih.gov/pubmed/30061498
http://dx.doi.org/10.3390/molecules23081899
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