3D-QSAR studies on UDP-glucuronosyltransferase 2B7 substrates using the pharmacophore and VolSurf approaches

Abstract

UDP-glucuronosyltransferase 2B7 (UGT2B7) is an important enzyme responsible for clearance of many drugs. Here, we report two 3D quantitative structure-activity relationship (QSAR) models for UGT2B7 using the pharmacophore and VolSurf approach, respectively.The dataset included 53 structurally diverse UGT2B7 substrates, 36 of which were used for the training set and 17 of which for the external test set. Pharmacophore-based 3D-QSAR model (or hypothesis) was developed using the Discovery Studio program. A user-defined “glucuronidation site” feature was forcefully included in a pharmacophore hypothesis. VolSurf-based 3D-QSAR model was generated using the VolSurf program. This involves calculation of VolSurf descriptors, variable selection with the FFD algorithm, and partial least squares (PLS) analyses.The best pharmacophore model (r2 = 0.736) consists of one glucuronidation site, one hydrogen bond acceptor, and three hydrophobic regions. Using this model, Km values for 14 of 17 test substrates were predicted within one log unit. The yielded VolSurf (PLS) model with two components shows statistical significance in both fitting and internal predicting (r2 = 0.866, q2 = 0.728). Further, the Km values for all test substrates were predicted within one log unit. In addition, the VolSurf model reveals an overlay of chemical features influencing the enzyme-substrate binding. Those include molecular size and shape, integy moments, capacity factors, best volumes of DRY probe, H-bonding, and log P.In conclusion, the pharmacophore and VolSurf approaches are successfully utilized to establish predictive models for UGT2B7. The derived models should be an efficient tool for high throughput prediction of UGT2B7 metabolism.