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

• Published in: Journal of biomolecular structure & dynamics Vol. 39; no. 11; pp. 4148 - 4159
• Main Authors: Jayaraj, John Marshal, Reteti, Everlyne, Kesavan, Chandrasekhar, Muthusamy, Karthikeyan
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 24.07.2021
• Subjects: 3D-QSAR; DFT; molecular docking and dynamics; VDR; virtual screening; 3D-QSAR; Virtual Screening; DFT; VDR; Molecular docking and dynamics
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2020.1775122

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 R 2 and Q 2 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