Department of Biochemistry, 72594Government College University, Faisalabad, Pakistan.
Department of Biochemistry, 66724University of Agriculture Faisalabad, Faisalabad, Pakistan.
Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:3946320221103120. doi: 10.1177/03946320221103120.
Diabetes mellitus is a heterogenous group of chronic metabolic disorders that results due to deficiency in insulin secretion and signalling. Multiple factors held responsible for onset of diabetes due to defects in glucose metabolism and cellular signalling mechanism. Over the past few years, many plant derived bioactive compounds have been recorded with increased efficacy and fewer side-effects against variety of diseases.
In the current study, molecular docking and molecular dynamics simulation approaches were employed to evaluate the tetrapeptides devised from AdMc1 protein of . Due to unavailability of appropriate template for modelling of 3D structure of AdMc1 protein, I-TASSER server was employed for prediction of good quality tertiary structure. Predicted model was refined by GalaxyRefine Web and evaluated by Verify 3D, ERRAT and Ramachandran plot analysis. Next, a ready-to-dock library of fifty tetrapeptides as potent inhibitors was prepared and docked against aldose reductase (AR), protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, α-amylase and glycogen synthase kinase 3-beta as receptor proteins. Molecular dynamics (MD) simulation was performed on Schrodinger's Desmond Module to check stability of the best docking complex.
Top five ligands were selected against each receptor protein based on their binding pattern and docking scores. Among selected ligands (i.e. VEID, TVEV, AYAY, EEIA, ITTV, TTIT, LPSM, RGIE, TTVE and EIAR) followed all parameters in drug scanning and ADMET screening tests. The MD simulations confirmed that the best selected peptide (i.e. VEID) docked with AR and PTP1B was structurally stable.
In the light of overall results of all analyses employed in this study, the selected ligands could be further processed as potential hypoglycaemic drug candidates.
糖尿病是一组异质性的慢性代谢紊乱疾病，由于胰岛素分泌和信号的缺乏而导致。多种因素导致葡萄糖代谢和细胞信号机制缺陷导致糖尿病的发生。在过去的几年中，许多植物衍生的生物活性化合物因其对多种疾病的疗效增加和副作用减少而被记录下来。
在本研究中，采用分子对接和分子动力学模拟方法来评估从 AdMc1 蛋白设计的四肽。由于缺乏建模 AdMc1 蛋白 3D 结构的适当模板，因此使用 I-TASSER 服务器来预测高质量的三级结构。预测模型通过 GalaxyRefine Web 进行细化，并通过 Verify 3D、ERRAT 和 Ramachandran 图分析进行评估。接下来，准备了一个包含五十个潜在抑制剂的四肽对接库，并将其对接在醛糖还原酶 (AR)、蛋白酪氨酸磷酸酶 1B (PTP1B)、α-葡萄糖苷酶、α-淀粉酶和糖原合酶激酶 3-β 作为受体蛋白上。在 Schrodinger 的 Desmond 模块上进行分子动力学 (MD) 模拟，以检查最佳对接复合物的稳定性。
根据结合模式和对接分数，从每个受体蛋白中选择了前五名配体。在所选择的配体（即 VEID、TVEV、AYAY、EEIA、ITTV、TTIT、LPSM、RGIE、TTVE 和 EIAR）中，所有配体都遵循药物筛选和 ADMET 筛选测试中的所有参数。MD 模拟证实，与 AR 和 PTP1B 对接的最佳选择肽 (即 VEID) 结构稳定。
根据本研究中使用的所有分析的综合结果，所选配体可以进一步作为潜在的降血糖药物候选物进行处理。
