Rathnayake Samith, Weerasinghe Samantha
Department of Chemistry, University of Colombo, Colombo, 00300, Sri Lanka.
J Mol Model. 2018 Nov 20;24(12):342. doi: 10.1007/s00894-018-3879-1.
The glucocorticoid receptors (GR) are members of the nuclear receptor superfamily that regulate growth, development, and many of the biological functions, including metabolism and inflammation, in a ligand dependent behavior. Thus, GRs are vital as therapeutic targets with steroid hormones and steroidal analogues, especially including the glucocorticoids. Studying the molecular mechanism of binding between GR and ligands is fundamentally important to develop applications in the pharmacological industry. The present study was carried out via molecular docking and molecular dynamic (MD) simulations of three GR-ligand complexes formed between the ligand binding domain (LBD) of GR with cortisol (a natural steroid), dexamethasone (a well-known synthetic steroid drug), and chonemorphine (a steroid virtually screened from the "Sri Lankan Flora" web-based information system). The investigation was mainly carried out in terms of macroscopic properties of the ligand-protein interactions and conformational fluctuations of the protein. The results indicated greater stability and a similar behavior of the GR protein in the chonemorphine-GR complex, compared to the other two complexes, GR-dexamethasone and GR-cortisol, in an aqueous medium. The integrity of the protein-substrate complexes was preserved by strong hydrogen bonds formed between the amino acid residues of the binding site of the proteins and ligands. The findings revealed that chonemorphine is a promising agonist to GR and may produce a pharmacological effect like that produced by glucocorticoids. Thus, the obtained knowledge could lead to further investigations of the pharmaceutical potential of chonemorphine and biological functions of GR in vivo.
糖皮质激素受体（GR）是核受体超家族的成员，以配体依赖的方式调节生长、发育以及包括代谢和炎症在内的许多生物学功能。因此，GR作为类固醇激素和类固醇类似物（尤其是糖皮质激素）的治疗靶点至关重要。研究GR与配体之间的结合分子机制对于制药行业的应用开发具有根本重要性。本研究通过对GR配体结合域（LBD）与皮质醇（一种天然类固醇）、地塞米松（一种著名的合成类固醇药物）和乔内吗啡（一种从基于网络的“斯里兰卡植物群”信息系统中虚拟筛选出的类固醇）形成的三种GR-配体复合物进行分子对接和分子动力学（MD）模拟来开展。该研究主要从配体-蛋白质相互作用的宏观性质和蛋白质的构象波动方面进行。结果表明，在水介质中，与其他两种复合物GR-地塞米松和GR-皮质醇相比，乔内吗啡-GR复合物中的GR蛋白具有更高的稳定性和相似的行为。蛋白质-底物复合物的完整性通过蛋白质结合位点的氨基酸残基与配体之间形成的强氢键得以保持。研究结果表明乔内吗啡是一种有前景的GR激动剂，可能产生与糖皮质激素类似的药理作用。因此，所获得的知识可能会引发对乔内吗啡的药物潜力以及GR在体内生物学功能的进一步研究。
