In silico studies on smoothened human receptor and its antagonists in search of anticancer effects

Abstract

Lately, the cancers related with abnormal hedgehog (Hh) signalling pathway are targeted by smoothened (SMO) receptor inhibitors that are rapidly developing. Still, the problems of known inhibitors such as severe side effects, weak potency against solid tumors or even the acquired resistance need to be overcome by developing new suitable inhibitors. To explore the structural requirements of antagonists needed for SMO receptor inhibition, pharma­co­phore mapping, 3D-QSAR models, database screening and docking studies were performed. The best selected pharmacophore hypothesis based on which statistically significant atom-based 3D-QSAR model was developed (R2 = 0.856, Q2 = 0.611 and Pearson-R = 0.817), was further subjected to dataset screening in order to evaluate its ability to prioritize active compounds over decoys. The efficiency of one four-points pharmacophore hypothesis (AAHR.524) was observed based on good evaluation metrics such as the area under the curve (0.795), and weighted average precision (0.835), suggesting that the model is trustworthy in predicting novel inhibitors against SMO receptor.