ADMET analysis of the top six ligands.

The simultaneous coexistence of complicated metabolic conditions like obesity and diabetes within an individual is known as diabesity. Obesity is the key factor for many chronic diseases, including insulin resistance and type 2 diabetes (T2D). Metabolic stress due to nutrient overload releases different inflammatory mediators. Secreted frizzled-related protein 4 (SFRP4) is also an inflammatory mediator that impairs insulin secretion. SFRP4 acts as an early biomarker for diabesity expressed with interleukin-1 beta (IL-1β) in the adipose tissues that hinder the exocytosis of insulin-secreting granules from the pancreatic β-cells and is a potential target for preserving β-cell dysfunction and the diabesity treatment. The current study aimed to screen potential bioactive compounds targeting and inhibiting the diabesity-linked SFRP4 protein through an in silico approach. The three-dimensional (3D) structure of human SFRP4 was predicted through comparative modeling techniques and evaluated by various online bioinformatics tools. The molecular docking and MD simulation investigations were carried out against phytochemicals with anti-diabetic and anti-obesity properties to shortlist the best SFRP4 inhibitor. Hesperetin, Curcumin, Isorhamnetin, Embelin, Epicatechin, and Methyl Eugenol interacted strongly with SFRP4 by displaying zero RMSD and binding affinities of -6.5, -6.4, -6.3, -5.3, -6.3 and -5.8 kcal/mol respectively. Additionally, the root mean square fluctuation and root mean square deviation graphs from the MD simulation results demonstrated that hesperetin has good variations throughout the simulation period as compared to others. This dynamic stability and control behavior of hesperetin, when it interacts with SFRP4, shows that it has the potential to modulate the function and activity of the protein. Therefore, hesperetin is identified as an effective and top drug candidate through this analysis for preserving beta-cell function and treating diabesity by targeting SFRP4. The findings of this study could be useful in the design and development of diabesity drugs.个体同时合并肥胖与糖尿病等复杂代谢紊乱的状态，被称为糖胖症（diabesity）。肥胖是包括胰岛素抵抗、2型糖尿病（T2D）在内的多种慢性疾病的核心诱因。营养过载引发的代谢应激会释放多种炎性介质。分泌型卷曲相关蛋白4（secreted frizzled-related protein 4, SFRP4）亦是一种炎性介质，可损伤胰岛素分泌功能。SFRP4作为糖胖症的早期生物标志物，与脂肪组织中的白细胞介素-1β（IL-1β）共同表达，能够抑制胰腺β细胞分泌胰岛素颗粒的胞吐过程，同时是改善β细胞功能障碍、治疗糖胖症的潜在靶点。 本研究旨在通过计算机模拟（in silico）方法，筛选可靶向并抑制糖胖症相关SFRP4蛋白的潜在生物活性化合物。研究人员采用比较建模技术预测了人源SFRP4的三维（3D）结构，并通过多款在线生物信息学工具对该结构进行了评估。针对具有抗糖尿病、抗肥胖活性的植物化学物开展了分子对接与分子动力学（MD）模拟研究，以筛选出最优的SFRP4抑制剂。 橙皮素、姜黄素、异鼠李素、恩贝素、表儿茶素与甲基丁香酚可与SFRP4发生较强相互作用，其均方根偏差（RMSD）均为0，结合亲和力分别为-6.5、-6.4、-6.3、-5.3、-6.3与-5.8 kcal/mol。此外，分子动力学模拟得到的均方根波动（RMSF）与均方根偏差曲线显示，相较于其他化合物，橙皮素在整个模拟周期内表现出良好的波动特性。橙皮素与SFRP4结合时展现出的动态稳定性与调控行为，表明其具备调节该蛋白功能与活性的潜力。因此，本分析鉴定出橙皮素为靶向SFRP4、改善β细胞功能并治疗糖胖症的高效优选候选药物。 本研究结果可为糖胖症治疗药物的设计与开发提供参考价值。