The binding mode prediction and similar ligand potency in the active site of Vitamin D Receptor (VDR) with QM/MM interaction, MESP and MD simulation

Abstract

Non-secosteroidal ligands are well-known Vitamin D Receptor agonists. In this study, we described a combined QM/MM to define the protein ligand interaction energy A strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activity. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from the present study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity.

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Different in silico approaches were applied to study the specific interactions of non-secosteroidal ligands in VDR active site. The article summarizes the importance of similar ligand efficacy and the distinct ligand potency in the VDR active site. The results could be useful for the designing of potent agonists in the lead optimization phase of drug discovery against VDR.

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