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

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.

SUBMITTER: Wan S

PROVIDER: S-EPMC7653344 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wan Shunzhou S Potterton Andrew A Husseini Fouad S FS Wright David W DW Heifetz Alexander A Malawski Maciej M Townsend-Nicholson Andrea A Coveney Peter V PV

Interface focus 20201016 6

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 A<sub>1</sub> and A<sub>2A</sub> 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 r ...[more]

PMID: 33178414

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Project description:A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high-resolution crystal structures of the target as starting points-something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A2A), and a protein-protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the "real" conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best.

Dataset Information

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

Publications

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

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