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Hit-to-lead and lead optimization binding free energy calculations for G protein-coupled receptors

Wan, S; Potterton, A; Husseini, FS; Wright, DW; Heifetz, A; Malawski, M; Townsend-Nicholson, A; (2020) Hit-to-lead and lead optimization binding free energy calculations for G protein-coupled receptors. Interface Focus , 10 (6) , Article 20190128. 10.1098/rsfs.2019.0128. Green open access

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Abstract

We apply the hit-to-lead ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and lead-optimization TIES (thermodynamic integration with enhanced sampling) methods to compute the binding free energies of a series of ligands at the A1 and A2A adenosine receptors, members of a subclass of the GPCR (G protein-coupled receptor) superfamily. Our predicted binding free energies, calculated using ESMACS, show a good correlation with previously reported experimental values of the ligands studied. Relative binding free energies, calculated using TIES, accurately predict experimentally determined values within a mean absolute error of approximately 1 kcal mol−1. Our methodology may be applied widely within the GPCR superfamily and to other small molecule–receptor protein systems.

Type: Article
Title: Hit-to-lead and lead optimization binding free energy calculations for G protein-coupled receptors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1098/rsfs.2019.0128
Publisher version: https://doi.org/10.1098/rsfs.2019.0128
Language: English
Additional information: Copyright © 2020 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, provided the original author and source are credited.
Keywords: molecular dynamics, ensemble simulations, G protein-coupled receptors, free energy, binding affinity prediction, adenosine receptors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10112756
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