3D-QSAR Studies on C24-Monoalkylated Vitamin D3 26,23-Lactones and their C2α-Modified Derivatives with Inhibitory Activity to Vitamin D Receptor

The ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) for 82 inhibitors of 25-dehydro-1α-hydroxyvitamin D3 -26,23-lactone analogs has been studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The established CoMFA model in training set gives a cross-validated q(2) value of 0.516 and a non-cross-validated rncv (2) value of 0.667, while the CoMSIA model results in q(2) =0.517 and rncv (2) =0.632. In general, the predictive ability of the CoMFA model is superior to that of the CoMSIA model, with rpred (2) =0.639 for the CoMFA and rpred (2) =0.619 for the CoMSIA model. Based on the CoMFA contour maps, some key structural characters of vitamin D3 analogs responsible for inhibitory activity are identified, and some new C2α-modified 24-alkylvitamin D3 lactone analogs with high predicted pIC50 values are designed. The ligand functional group mutations by FEP simulation and docking studies reveal the rationality of the molecular design.