Extracting structural requirements for activity of GPR119 agonists: a hologram quantitative structure activity relationship (HQSAR) study

Abstract

GPR119 is a potential target for the treatment of diabetes mellitus. GPR119 agonists minimize the side-effects observed with sulphonyl ureas and glucagon-like peptide 1 analogs. Various reported GPR119 agonists from various patents were selected for the study and a 2D-QSAR study (HQSAR) was carried out. Fifty-five molecules were selected for the study. The study was performed on a training set of 40 structurally diverse molecules with reported biological activity. The most significant HQSAR model (q2 = 0.87, r2 = 0.99) was obtained using atoms, bond, connection, and acceptor and donor as fragment distinction. The fragment size was kept at 4–7. The predictive ability of the model was evaluated by an external test set containing 15 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The important fragments determined by the study were used to design new drug candidates having increased biological activity and comparable physicochemical properties.