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The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM / MM Interaction, MESP , and MD Simulation
Author(s) -
Selvaraman Nagamani,
Selvam Saravana Kumar,
Muthusamy Karthikeyan
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12754
Subject(s) - calcitriol receptor , chemistry , agonist , docking (animal) , ligand (biochemistry) , molecular dynamics , stereochemistry , steric effects , receptor , molecular model , interaction energy , potency , biophysics , biochemistry , in vitro , molecule , computational chemistry , biology , medicine , nursing , organic chemistry
Non‐secosteroidal ligands are well‐known vitamin D receptor (VDR) 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 activities. 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 this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity.