Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field

Silvia A Martins; Sergio F Sousa; Maria João Ramos; Pedro A Fernandes

doi:10.1021/ct500346y

Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field

J Chem Theory Comput. 2014 Aug 12;10(8):3570-7. doi: 10.1021/ct500346y.

Authors

Silvia A Martins¹, Sergio F Sousa¹, Maria João Ramos¹, Pedro A Fernandes¹

Affiliation

¹ REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto , Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.

PMID: 26588320
DOI: 10.1021/ct500346y

Abstract

Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The determination of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (ΔΔGsolv) for a total of 92 transformations in small molecules was predicted using Thermodynamic Integration (TI). It was our aim to compare experimental and calculated solvation free energies for typical and prime additions considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between experimental and predicted values, with an overestimation of the predicted values for CH3, halogens, and NH2, as well as an underestimation for CONH2, but all fall within ±1 kcal/mol. NO2 addition showed a larger and systematic underestimation of the predicted ΔΔGsolv, indicating the need for special attention in these cases. For small molecules, if no experimental data is available, using TI as a theoretical strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy.