Structural insights on vitamin D receptor and screening of new potent agonist molecules: structure and ligand-based approach

Vitamin D deficiency is one of the common clinical symptoms of severe chronic kidney disease (CKD) patients. Vitamin D receptor (VDR) is a part of the nuclear receptor family exerts vitamin D activation to maintain calcium/phosphorous homeostasis and bone metabolism. The reduction of VDR activity leads to vitamin D deficiency. In this study, we found three potent agonists for VDR protein on the structure and ligand-based screening methods. In the structure-based method, 792 compounds were screened. A 5-point pharmacophore (one hydrogen bond acceptor, two hydrophobic and aromatic rings (AHHRR)) was developed and used to obtain a predictive 3 D-Quantitative structure-activity relationship (QSAR), model. The acquire R² and Q² values are 0.8676 and 0.8523 respectively. Further, E-pharmacophore based screening, molecular docking (binding affinity), Molecular Mechanics-Generalized Born Surface Area (binding free energy), chemical reactivity (Density Functional Theory (DFT) study) and molecular dynamics (protein-ligand stability) analysis were done. Hence, the computational investigations demonstrate that the identified ligands such as TCM_1875, TCM_1874, and TCM_2868 showed promising agonist effect on VDR protein. Further validation and experiments need to be done to confirm the potency of the identified compounds shortly. Communicated by Ramaswamy H. Sarma.