基于酚的PTP1B变张抑制:释放代谢紊乱的新治疗潜力。

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Emadeldin M Kamel, Ahmed A Allam, Hassan A Rudayni, Fahad M Alshabrmi, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi
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引用次数: 0

摘要

蛋白酪氨酸磷酸酶1B (PTP1B)在胰岛素信号传导中起关键作用,并与包括2型糖尿病在内的多种代谢疾病相关。在这项研究中,我们研究了从柽柳中分离的5种酚类化合物对PTP1B的抑制潜力。通过分子对接、分子动力学(MD)模拟和ADMET分析,我们评估了这些化合物的结合模式、稳定性和药代动力学性质。结果表明,3,3′-二- o -甲基甲酸和灯花苷的抑菌活性最强,IC50值分别为3.77±0.15µM和3.08±0.36µM。两种化合物均通过非竞争性抑制作用抑制PTP1B, Ki值分别为3.90µM和3.40µM。自由能景观(FEL)分析证实了稳定的结合构象,而各种MD参数分析表明酶的结构扰动最小,表明酶-配体复合物的稳定性增强。MM/PBSA计算进一步支持这些化合物的强结合亲和力,突出了它们作为PTP1B抑制剂的潜力。ADMET分析显示良好的药代动力学特性,包括良好的生物利用度和低毒性风险。本研究为柽柳酚类化合物作为PTP1B抑制药物的潜力提供了强有力的证据,为代谢性疾病的治疗提供了新的机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phenolic-based allosteric inhibition of PTP1B: unlocking new therapeutic potential for metabolic disorders.

Protein tyrosine phosphatase 1B (PTP1B) plays a critical role in insulin signaling and is associated with various metabolic diseases, including type 2 diabetes. In this study, we investigated the inhibitory potential of five phenolic compounds isolated from Tamarix aphylla against PTP1B. Using molecular docking, molecular dynamics (MD) simulations, and ADMET analysis, we assessed the binding modes, stability, and pharmacokinetic properties of these compounds. The findings from in silico studies were validated by experimental in vitro enzyme activity assays, which showed that 3,3'-di-O-methylellagic acid and scutellarein exhibited the strongest inhibitory activities with IC50 values of 3.77 ± 0.15 µM and 3.08 ± 0.36 µM, respectively. Both compounds were found to inhibit PTP1B via non-competitive inhibition, with Ki values of 3.90 µM and 3.40 µM. The free energy landscape (FEL) analysis confirmed stable binding conformations, while various MD parameter analyses indicated minimal structural perturbations in the enzyme, suggesting enhanced stability of the enzyme-ligand complexes. MM/PBSA calculations further supported the strong binding affinities of these compounds, highlighting their potential as PTP1B inhibitors. ADMET profiling indicated favorable pharmacokinetic properties, including good bioavailability and low toxicity risks. This study provides compelling evidence for the potential of phenolic compounds from Tamarix aphylla as therapeutic agents for PTP1B inhibition, offering new opportunities for the treatment of metabolic disorders.

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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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