Towards a critical evaluation of an empirical and volume-based solvation function for ligand docking.

Abstract

Molecular docking is an important tool for the discovery of new biologically active molecules given that the receptor structure is known. An excellent environment for the development of new methods and improvement of the current methods is being provided by the rapid growth in the number of proteins with known structure. The evaluation of the solvation energies outstands among the challenges for the modeling of the receptor-ligand interactions, especially in the context of molecular docking where a fast, though accurate, evaluation is ought to be achieved. Here we evaluated a variation of the desolvation energy model proposed by Stouten (Stouten P.F.W. et al, Molecular Simulation, 1993, 10: 97–120), or SV model. The SV model showed a linear correlation with experimentally determined solvation energies, as available in the database FreeSolv. However, when used in retrospective docking simulations using the benchmarks DUD, charged-matched DUD and DUD-Enhanced, the SV model resulted in poorer enrichments when compared to a pure force field model with no correction for solvation effects. The data provided here is consistent with other empirical solvation models employed in the context of molecular docking and indicates that a good model to account for solvent effects is still a goal to achieve. On the other hand, despite the inability to improve the enrichment of retrospective simulations, the SV solvation model showed an interesting ability to reduce the number of molecules with net charge -2 and -3 e among the top-scored molecules in a prospective test.