Kamel Emadeldin M, Abdelrheem Doaa A, Ahmed Noha A, Alshabrmi Fahad M, Aba Alkhayl Faris F, Alwaili Maha A, Altoom Naif G, Lamsabhi Al Mokhtar
Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt.
Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.
Protein J. 2025 Jul 16. doi: 10.1007/s10930-025-10272-x.
A phytochemical investigation of Glycyrrhiza echinata led to the isolation and structural characterization of twelve phenolic compounds. An in silico target fishing analysis identified protein tyrosine phosphatase 1B (PTP1B) as a potential biological target for these phytochemicals, prompting an in vitro evaluation of their PTP1B inhibitory activities. Gancaonin Q and licoflavone C exhibited notably low IC₅₀ values (1.61 ± 0.32 µM and 1.39 ± 0.33 µM, respectively), outperforming the reference inhibitor ursolic acid (IC₅₀ = 7.17 ± 0.69 µM), while norartocarpetin showed moderate activity (IC₅₀ = 42.41 ± 2.12 µM). Enzyme kinetic studies revealed that gancaonin Q and licoflavone C act as noncompetitive inhibitors of PTP1B. Subsequent in silico analyses supported these findings and provided mechanistic insights. Molecular docking confirmed robust binding interactions for gancaonin Q and licoflavone C at the PTP1B allosteric site. Free energy landscape (FEL) calculations indicated that both compounds stabilized the enzyme within low-energy conformations, and MM/PBSA estimations corroborated their favorable binding free energies. Molecular dynamics simulations further demonstrated the stability of the ligand-enzyme complexes, characterized by reduced structural fluctuations in comparison with the free enzyme and norartocarpetin-bound states. Finally, ADMET assessments indicated promising pharmacokinetic and toxicity profiles, with some scope for structural refinement. Overall, these results highlight gancaonin Q and licoflavone C as promising lead compounds for the development of PTP1B inhibitors with therapeutic potential.
对刺果甘草进行植物化学研究，分离并鉴定了12种酚类化合物的结构。计算机模拟靶点筛选分析确定蛋白酪氨酸磷酸酶1B（PTP1B）是这些植物化学物质的潜在生物学靶点，促使对其PTP1B抑制活性进行体外评估。甘草宁Q和甘草黄酮C表现出极低的IC₅₀值（分别为1.61±0.32 μM和1.39±0.33 μM），优于参考抑制剂熊果酸（IC₅₀ = 7.17±0.69 μM），而去甲波罗蜜黄素表现出中等活性（IC₅₀ = 42.41±2.12 μM）。酶动力学研究表明，甘草宁Q和甘草黄酮C作为PTP1B的非竞争性抑制剂。随后的计算机模拟分析支持了这些发现，并提供了作用机制的见解。分子对接证实甘草宁Q和甘草黄酮C在PTP1B变构位点有强大的结合相互作用。自由能景观（FEL）计算表明，这两种化合物都使酶稳定在低能量构象中，MM/PBSA估计证实了它们有利的结合自由能。分子动力学模拟进一步证明了配体 - 酶复合物的稳定性，其特征是与游离酶和去甲波罗蜜黄素结合状态相比，结构波动减小。最后，ADMET评估表明其具有良好的药代动力学和毒性特征，在结构优化方面有一定空间。总体而言，这些结果突出了甘草宁Q和甘草黄酮C作为开发具有治疗潜力的PTP1B抑制剂的有前景的先导化合物。
