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.
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