Selvaraman Nagamani, Selvam Saravana Kumar, Muthusamy Karthikeyan
Pharmacogenomics and CADD Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, 630 004, India.
Chem Biol Drug Des. 2016 Aug;88(2):272-80. doi: 10.1111/cbdd.12754. Epub 2016 Mar 31.
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.
非甾体类配体是众所周知的维生素D受体（VDR）激动剂。在本研究中，我们描述了一种结合量子力学/分子力学（QM/MM）的方法来定义蛋白质-配体相互作用能，QM-MM相互作用能和结合自由能与生物活性之间存在很强的正相关性。进行了分子动力学模拟研究，并对特定相互作用进行了广泛研究。分子对接结果和表面分析揭示了这些非甾体类配体与VDR的空间和静电互补性。最后，还计算了药物相似性性质，发现其在可接受范围内。结果表明，侧链上的大基团取代会降低VDR活性，而小取代则会增加VDR活性。对H393A和H301A突变的功能分析证实了它们在VDR激动和拮抗活性中的作用。除了His393和His301外，铰链区的另外两个氨基酸，即Ser233和Arg270，在不同的配体效力中作为激动剂特有的电子供体/受体。本研究结果揭示了VDR激动剂的结合机制以及提高选择性所需的结构修饰。
