Selvaraman Nagamani, Chandrasekhar Kesavan and Karthikeyan Muthusamy* Pages 329 - 343 ( 15 )
Aim and Objective: 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 been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence 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.
Materials and Methods: Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR.
Results: The result shows that, AM1 is the good charge model for our study and 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.
Conclusion: Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.
Vitamin D receptor, 3D-QSAR, empirical and semi-empirical calculations, AM1, induced fit docking, vitamin D analogues.
Deparment of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamil Nadu, Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, CA 92357, Deparment of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamil Nadu