Solvation free energy arithmetic for small organic molecules. Issue 13 (3rd March 2023)

• Record Type: Journal Article
• Authors: Lazaric, Aleksandar; Pattni, Viren; Fuegner, Kaprao; Ben‐Naim, Arieh; Heyden, Matthias
• Is Part Of: Journal of computational chemistry. Volume 44:Issue 13(2023)
• Page Start: 1263
• Page End: 1277
• Publication Date: 2023-03-03
• Subjects: computational drug design -- solvation thermodynamics; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.27081
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract: Solvent‐mediated interactions contribute to ligand binding affinities in computational drug design and provide a challenge for theoretical predictions. In this study, we analyze the solvation free energy of benzene derivatives in water to guide the development of predictive models for solvation free energies and solvent‐mediated interactions. We use a spatially resolved analysis of local solvation free energy contributions and define solvation free energy arithmetic, which enable us to construct additive models to describe the solvation of complex compounds. The substituents analyzed in this study are carboxyl and nitro‐groups due to their similar sterical requirements but distinct interactions with water. We find that nonadditive solvation free energy contributions are primarily attributed to electrostatics, which are qualitatively reproduced with computationally efficient continuum models. This suggests a promising route for the development of efficient and accurate models for the solvation of complex molecules with varying substitution patterns using solvation arithmetic. Abstract : Based on a spatially resolved analysis of solvation free energy densities, we define solvation free energy arithmetic to construct additive solvation models for complex organic molecules. We find that nonadditive solvation free energy contributions are primarily caused by electrostatic solute‐water interactions that can be estimated with continuum models. We propose the use of solvation free energy arithmetic to predict the solvation of lead compounds in computational drug design with a large number of possible functionalizations.