Balaji Hari, Selvaraj A, Saha Niladri, Sundar P Shyam, Jubie S, Mohankumar Suresh K
TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil nadu, India.
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil nadu, India.
Mini Rev Med Chem. 2021;21(17):2612-2625. doi: 10.2174/1389557521666210104170408.
Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor's (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence reports that selective long chain polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We, therefore, hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective of the deficiency of vitamin-D. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.
维生素D缺乏是一个全球性问题。维生素D受体（VDR）配体结合域（LBD）中的基因突变会不同程度地改变配体结合亲和力、与视黄酸X受体（RXR）的异二聚化，并抑制共激活因子相互作用。这些LBD突变可能导致部分或完全激素无反应性。大量证据表明，包括二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）和花生四烯酸（AA）在内的选择性长链多不饱和脂肪酸（PUFA）与VDR的配体结合域结合并导致转录激活。因此，我们假设选择性PUFA会调节VDR的动力学和动力学，而与维生素D缺乏无关。通过计算机对接研究检查了所选PUFA在VDR活性位点的空间排列。对接结果表明，PUFA对VDR具有脂肪酸结构特异性结合亲和力。在野生型VDR（PDB编号：2ZLC）中，计算出的EPA、DHA和AA结合能（Cdocker能量）与维生素D相比更低。值得注意的是，与标准维生素D相比，DHA与突变型VDR（PDB编号：3VT7）的结合相互作用更高。利用分子动力学模拟来确认DHA与突变型VDR复合物潜在化合物结合的稳定性。这些发现表明PUFA在VDR激活中的独特作用，并可能提供规避维生素D缺乏的替代策略。
