Babu B, Divakar S, Gowramma B, Jupudi Srikanth, Chand Jagdish, Malakar Kumar Vishnu
Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India.
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India.
J Biomol Struct Dyn. 2025 Feb;43(2):694-708. doi: 10.1080/07391102.2023.2283161. Epub 2023 Nov 24.
Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from β-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one's moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (-13.9 kcal/mol and -86.2 kcal/mol), A1 (-11.1 kcal/mol and -79.5 kcal/mol), A13 (-11.3 kcal/mol and -91.4 kcal/mol), and the co-crystal itself (-9.8 kcal/mol and -76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and β-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein.Communicated by Ramaswamy H. Sarma.
2型糖尿病是一种双相代谢紊乱疾病，其特征是β细胞胰岛素分泌异常和胰岛素抵抗。噻唑烷二酮类是一类有效的抗糖尿病药物，通过调节过氧化物酶体增殖物激活受体γ（PPARγ，一种核受体）发挥作用。然而，它们的完全激动活性会通过与TYR473残基形成强氢键来稳定螺旋12，从而导致严重的副作用。如现有数据报道，部分和选择性PPARγ调节剂（GW0072、GQ16、VSP - 51、MRL - 20、MBX - 213、INT131）与完全激动剂相比已显示出更优的效果，且不会产生不良反应。为了解决这一不确定性并推进治疗方案，我们基于酚类和噻唑烷 - 4 - 酮部分的杂化结构，鉴定并设计了一类新型化合物（A1 - A23）。我们合理的药物设计策略纳入了构效关系原理，并通过计算均方根偏差验证了对接研究。此外，我们进行了分子对接、结合能、分子动力学模拟以及分子动力学后计算，以评估配体与蛋白质之间的动力学行为。所选配体显示出非常有利的对接分数和结合能，分别与共晶体（罗格列酮）相当，如A12（-13.9 kcal/mol和-86.2 kcal/mol）、A1（-11.1 kcal/mol和-79.5 kcal/mol）、A13（-11.3 kcal/mol和-91.4 kcal/mol），以及共晶体本身（-9.8 kcal/mol和-76 kcal/mol）。最后，分子动力学模拟表明，所选配体对螺旋12和β折叠的稳定作用相当。得出的结论是，设计的配体（A12、A1和A13）与特定残基TYR473的氢键相互作用较弱，这部分调节了PPARγ蛋白。由Ramaswamy H. Sarma传达。
