Comparative Molecular Field Analysis Using Molecular Integral Equation Theory.

ABSTRACT

Recently, Güssregen et al. used solute-solvent distribution functions calculated by the three-dimensional Reference Interaction Site Model (3DRISM) in a 3D quantitative structure-activity relationship (QSAR) approach to model activity data for a set of serine protease inhibitors; this approach was referred to as Comparative Analysis of 3D RISM Maps (CARMa). [ J. Chem. Inf. MODEL 2017, 57, 1652-1666] Here we extend this idea by introducing probe atoms into the 3DRISM solvent model in order to directly capture other molecular interactions in addition to those related to hydration/dehydration. Benchmark results for six different protein-ligand systems show that CARMa models trained on probe atom descriptors give consistently more accurate predictions than Comparative Molecular Field Analysis (CoMFA) and other common QSAR approaches.