Prediction of toluene/water partition coefficients of SAMPL9 compounds: comparison of the molecular dynamics force fields GAFF/RESP and GAFF/IPolQ-Mod + LJ-fit

Abstract

The SAMPL9 blind challenge aims to predict the toluene/water partition coefficient of 16 active pharmaceutical ingredients. In this work, the transfer free energy between the solvation in water and toluene is predicted by molecular dynamics simulations using the MBAR method [M. R. Shirts and J. D. Chodera, J. Chem. Phys., 2008, 129, 123105] with replica exchange molecular dynamics [Y. Sugita, A. Kitao and Y. Okamoto, J. Chem. Phys., 2000, 113, 6042–6051]. Thereby, simulation results using the force field GAFF/IPolQ-Mod + LJ-fit [A. Mecklenfeld and G. Raabe, ADMET and DMPK, 2020, 8, 274–296] are compared to simulations with the standard GAFF/RESP model [J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman and D. A. Case, J. Comput. Chem., 2004, 25, 1157–1174]. By statistical evaluation of RMSD and R², we compare the results with other participants of the blind challenge. Furthermore, we provide a detailed analysis of solvation structures using the combined distribution function for simulations in water and the plane projection analysis for simulations in toluene, and we work out differences and similarities of the two force fields. These studies allow to gain important insights to increase the understanding of the mechanism of interactions between the drugs and the solvent.