Assessment of GAFF2 and OPLS-AA general force fields in combination with the water models TIP3P, SPCE and OPC3 for the solvation free energy of drug-like organic molecules

Molecular dynamics simulations have been performed to compute the solvation free energy and the octanol/water partition coefficients for a challenging set of selected organic molecules, characterized by the simultaneous presence of functional groups coarsely spanning a large portion of the chemical space in drug-like compounds and, in many cases, by a complex conformational landscape (2-propoxyethanol, acetylsalicylic acid, cyclohexanamine, dialifor, ketoprofen, nitralin, profluralin, terbacil). OPLS-AA and GAFF2 parameterizations of the organic molecules and of 1-octanol have been done via the web-based automatic parameter generators, LigParGen [Dodda et al. Nucl. Acids Res. 2017; 121, 3864] and PrimaDORAC [Procacci, J. Chem. Inf. Model. 2017; 57, 1240], respectively. For the water solvent, three popular three-point sites models, TIP3P, SPCE and OPC3, were tested. Solvation free energies in water and 1-octanol are evaluated using a recently developed non equilibrium alchemical technology [Procacci et al. J. Chem. Theory Comput. 2014; 10, 2813]. Extensive and accurate simulations including all possible combinations of organic molecule, solvent and solvent model, allowed to assess the accuracy with regard to solvation free energies of the latest release of two widespread force fields, OPLS and GAFF. The collected data are relevant in the evaluation of the predictive power of these classical force fields (and of the related support software for automated parameterization) with regard to binding free energies in drug-receptor system for industrial applications.