Kamel Emadeldin M, Othman Sarah I, Alkhayl Faris F Aba, Alshabrmi Fahad M, Allam Ahmed A, Ahmed Noha A, Lamsabhi Al Mokhtar
Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514 Egypt.
Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, 11671 Riyadh, Saudi Arabia.
3 Biotech. 2025 Jun;15(6):168. doi: 10.1007/s13205-025-04326-1. Epub 2025 May 15.
In this study, we measured the inhibitory potential of six coumarins against aldose reductase using both computational and experimental approaches. Molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations identified auraptene, marmesin, and isopimpinellin as the most promising inhibitors, with binding affinities of ΔG = -34.88, -29.40, and -20.31 kcal/mol, respectively. ADMET analysis indicated favorable pharmacokinetic properties for all three compounds, including high gastrointestinal absorption and bioavailability. In vitro assays confirmed auraptene as the most potent inhibitor with the lowest IC (1.43 ± 0.14 µM), outperforming quercetin (IC = 2.50 ± 0.31 µM). Marmesin and isopimpinellin showed IC values of 3.80 ± 0.1 µM and 5.71 ± 0.8 µM, respectively. Kinetic studies revealed auraptene as a noncompetitive inhibitor (K = 1.84 µM), isopimpinellin as a competitive inhibitor (K = 1.83 µM), and marmesin as a mixed inhibitor (K = 2.32 µM). These results suggest auraptene and marmesin as potential lead compounds for AR inhibition with strong binding affinities and favorable pharmacokinetic profiles.
在本研究中，我们使用计算和实验方法测量了六种香豆素对醛糖还原酶的抑制潜力。分子对接、分子动力学模拟和MM/PBSA结合自由能计算确定奥瑞烯、异茴芹内酯和异欧前胡素是最有前景的抑制剂，其结合亲和力分别为ΔG = -34.88、-29.40和-20.31 kcal/mol。ADMET分析表明这三种化合物均具有良好的药代动力学性质，包括高胃肠道吸收和生物利用度。体外试验证实奥瑞烯是最有效的抑制剂，IC（1.43 ± 0.14 µM）最低，优于槲皮素（IC = 2.50 ± 0.31 µM）。异茴芹内酯和异欧前胡素的IC值分别为3.80 ± 0.1 µM和5.71 ± 0.8 µM。动力学研究表明奥瑞烯是一种非竞争性抑制剂（K = 1.84 µM），异欧前胡素是一种竞争性抑制剂（K = 1.83 µM），异茴芹内酯是一种混合型抑制剂（K = 2.32 µM）。这些结果表明，奥瑞烯和异茴芹内酯具有较强的结合亲和力和良好的药代动力学特征，是抑制醛糖还原酶的潜在先导化合物。
