Combined Linear Interaction Energy and Alchemical Solvation Free-Energy Approach for Protein-Binding Affinity Computation.
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Key Findings
Abstract
Calculating free energies of binding (Δ) between ligands and their target protein is of major interest to drug discovery and safety, yet it is still associated with several challenges and difficulties. Linear interaction energy (LIE) is an efficient in silico method for Δ computation. LIE models can be trained and used to directly calculate binding affinities from interaction energies involving ligands in the bound and unbound states only, and LIE can be combined with statistical weighting to calculate Δ for flexible proteins that may bind their ligands in multiple orientations. Here, we investigate if LIE predictions can be effectively improved by explicitly including the entropy of (de)solvation into our free-energy calculations. For that purpose, we combine LIE calculations for the protein-ligand-bound state with explicit free-energy perturbation to rigorously compute the unbound ligand's solvation free energy. We show that for 28 Cytochrome P450 2A6 (CYP2A6) ligands, coupling LIE with alchemical solvation free-energy calculation helps to improve obtained correlation between computed and reference (experimental) binding data.
Affiliation
AIMMS Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.
External References
- PubMed ID:
- 31894691
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