Amity Institute of Environmental Sciences, Amity University, Noida 201303, India.
Academy of Biology and Biotechnology, Southern Federal University, 344006 Rostov-on-Don, Russia.
Molecules. 2022 Mar 29;27(7):2212. doi: 10.3390/molecules27072212.
The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure-activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of -7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be -7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance.
2 型糖尿病（T2DM）病例的增加以及与化学/合成药物副作用相关的并发症引起了人们对药物安全性的关注。因此，迫切需要探索和确定天然生物活性化合物作为替代药物。蛋白酪氨酸磷酸酶 1B（PTP1B）作为负调节剂起作用，因此被认为是调节胰岛素信号和胰岛素抵抗的关键蛋白质靶标之一。本文涉及针对 PTP1B 活性筛选多酚数据库，以鉴定潜在的抑制剂。研究计划有两个明确的目标。在第一个目标下，我们对具有 PTP1B 的黄酮类化合物进行了定量构效关系分析，结果表明芳香键（naro）的数量与 PTP1B 的抑制浓度（IC）之间存在最强相关性（R = 93.25%）。第二个目标强调了使用分子对接、分子动力学（MD）模拟和自由能估算来研究所选多酚类化合物对 PTP1B 活性的结合潜力。在所研究的多酚类化合物中，黄酮木脂素 silydianin 被鉴定为一种先导化合物，具有类药性，具有更高的负结合能（-7.235 kcal/mol）和 pKd 值为 5.2。基于自由能的结合亲和力（ΔG）估计为-7.02 kcal/mol。MD 模拟揭示了相互作用残基（Gly183、Arg221、Thr263 和 Asp265）的稳定性。结果表明，所鉴定的多酚 silydianin 可以作为一种有前途的天然 PTP1B 抑制剂，调节胰岛素抵抗。
