Selvaraman Nagamani, Chandrasekhar Kesavan and Muthusamy Karthikeyan*
Vitamin D3 (1, 25(OH) 2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influenced the structure based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR. The result shows that, AM1 is the good charge model for our study. 3D quantitative structure activity relationship (3D – QSAR) model was generated for 38 Vitamin D analogues and structure and pharmacophore based QSAR was performed. The results revealed that AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity. Overall we found that, charge based optimizations of ligands were out performed than the pharmacophore based QSAR model.
VDR, 3D-QSAR, Empirical and Semi-empirical calculations, AM1, Induced Fit Docking.
Deparmentt of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamilnadu, Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, CA 92357, Deparmentt of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamilnadu