Kamel Emadeldin M, Othman Sarah I, Rudayni Hassan A, Allam Ahmed 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 Riyadh 11671 Saudi Arabia.
RSC Adv. 2025 Feb 6;15(5):3829-3848. doi: 10.1039/d4ra09076d. eCollection 2025 Jan 29.
Squalene epoxidase (SQLE) is a crucial enzyme in the sterol biosynthesis pathway and a promising target for therapeutic intervention in hypercholesterolemia and fungal infections. This study evaluates the inhibitory potential of six flavonoids namely silibinin, baicalin, naringenin, chrysin, apigenin-7-O-glucoside, and isorhamnetin against SQLE using an integrative approach combining and experimental methods. Molecular docking revealed that apigenin-7-O-glucoside, silibinin, and baicalin displayed the highest binding affinities (-10.7, -10.2, and -10.0 kcal mol, respectively) and robust interactions with the SQLE binding site. These findings were corroborated by 200 ns molecular dynamics (MD) simulations, which demonstrated stable binding trajectories, minimal structural fluctuations, a thermodynamically favored potential energy landscape (PEL) and favorable MM/PBSA binding free energies for three flavonoids. Experimental validation inhibition assays confirmed the computational predictions, with apigenin-7-O-glucoside emerging as the most potent inhibitor (IC = 1.74 ± 0.05 μM), followed by silibinin (IC = 1.88 ± 0.28 μM) and baicalin (IC = 2.50 ± 0.46 μM). Enzyme kinetics studies revealed distinct mechanisms of action: apigenin-7-O-glucoside exhibited competitive inhibition, while silibinin and baicalin showed mixed inhibition. Furthermore, ADMET analysis indicated favorable pharmacokinetic and pharmacodynamic profiles for these flavonoids, with silibinin demonstrating particularly high bioavailability and lipophilicity. This study highlights apigenin-7-O-glucoside, silibinin, and baicalin as potent SQLE inhibitors with promising therapeutic potential. The congruence between predictions and experimental results underscores the reliability of computational approaches in drug discovery, paving the way for future preclinical development of these compounds as novel SQLE-targeted therapeutics.
角鲨烯环氧酶（SQLE）是甾醇生物合成途径中的一种关键酶，也是高胆固醇血症和真菌感染治疗干预的一个有前景的靶点。本研究采用结合计算和实验方法的综合方法，评估了水飞蓟宾、黄芩苷、柚皮素、白杨素、芹菜素 -7-O-葡萄糖苷和异鼠李素六种黄酮类化合物对SQLE的抑制潜力。分子对接显示，芹菜素 -7-O-葡萄糖苷、水飞蓟宾和黄芩苷表现出最高的结合亲和力（分别为 -10.7、-10.2和 -10.0 kcal/mol），并与SQLE结合位点有强烈的相互作用。200纳秒的分子动力学（MD）模拟证实了这些发现，该模拟显示了三种黄酮类化合物稳定的结合轨迹、最小的结构波动、热力学上有利的势能面（PEL）以及有利的MM/PBSA结合自由能。实验验证抑制试验证实了计算预测结果，芹菜素 -7-O-葡萄糖苷成为最有效的抑制剂（IC = 1.74 ± 0.05 μM），其次是水飞蓟宾（IC = 1.88 ± 0.28 μM）和黄芩苷（IC = 2.50 ± 0.46 μM）。酶动力学研究揭示了不同的作用机制：芹菜素 -7-O-葡萄糖苷表现出竞争性抑制，而水飞蓟宾和黄芩苷表现出混合抑制。此外，ADMET分析表明这些黄酮类化合物具有良好的药代动力学和药效学特征，水飞蓟宾表现出特别高的生物利用度和亲脂性。本研究强调了芹菜素 -7-O-葡萄糖苷、水飞蓟宾和黄芩苷作为具有潜在治疗潜力的强效SQLE抑制剂。计算预测与实验结果之间的一致性强调了药物发现中计算方法的可靠性，为这些化合物作为新型SQLE靶向治疗药物的未来临床前开发铺平了道路。
