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.
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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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