Alruhaimi Reem S, Kamel Emadeldin M, Alnasser Sulaiman M, Alzoghaibi Mohammed A, Lamsabhi Al Mokhtar, Mahmoud Ayman M
Department of Biology, College of Science, Princess Nourah bint Abdulrahman University Riyadh 11671 Saudi Arabia.
Organic Chemistry Department, Faculty of Science, Beni-Suef University Beni-Suef 62514 Egypt.
RSC Adv. 2024 Oct 23;14(45):33602-33618. doi: 10.1039/d4ra05984k. eCollection 2024 Oct 17.
Given the critical role of carbonic anhydrase IX (CA IX) in various pathological conditions, there is a significant demand for new inhibitors to enhance patient outcomes and clinical management. In this study, we examined the inhibitory effectiveness of five coumarins derived from against CA IX using assays and computational modeling. Among the coumarins tested, xeroboside and isobaisseoside were identified as the most potent inhibitors. Kinetic studies indicated that xeroboside and isobaisseoside exhibit a mixed inhibition mode. Molecular docking analysis showed that the tested coumarins exhibit binding affinities and extensive polar interactions with CA IX. These coumarins demonstrated significant hydrophobic interactions and occupied the same binding site as acetazolamide (AAZ). Molecular dynamics (MD) indicated that xeroboside and isobaisseoside exhibited consistent trajectories and notable energy stabilization during their interaction with CA IX. MM/PBSA calculations showed that xeroboside displayed the lowest binding free energy (-27.26 ± 2.48 kJ mol). Potential Energy Landscape (PEL) analysis revealed distinct and stable conformational states for the CA IX-ligand complexes, with xeroboside exhibiting the most stable and lowest energy configuration. These computational findings are consistent with the experimental results, highlighting the potential efficacy of xeroboside and isobaisseoside as CA IX inhibitors. In conclusion, -derived coumarins are promising candidates as effective CA IX inhibitors.
鉴于碳酸酐酶IX（CA IX）在各种病理状况中的关键作用，对新型抑制剂的需求极为迫切，以改善患者预后并优化临床管理。在本研究中，我们使用实验和计算模型研究了五种源自[具体来源未提及]的香豆素对CA IX的抑制效果。在所测试的香豆素中，异欧前胡素和异紫花前胡苷被鉴定为最有效的抑制剂。动力学研究表明，异欧前胡素和异紫花前胡苷呈现混合抑制模式。分子对接分析表明，所测试的香豆素与CA IX表现出结合亲和力和广泛的极性相互作用。这些香豆素表现出显著的疏水相互作用，并与乙酰唑胺（AAZ）占据相同的结合位点。分子动力学（MD）表明，异欧前胡素和异紫花前胡苷在与CA IX相互作用期间呈现出一致的轨迹和显著的能量稳定。MM/PBSA计算表明，异欧前胡素显示出最低的结合自由能（-27.26 ± 2.48 kJ/mol）。势能景观（PEL）分析揭示了CA IX-配体复合物不同且稳定的构象状态，异欧前胡素表现出最稳定且能量最低的构型。这些计算结果与实验结果一致，突出了异欧前胡素和异紫花前胡苷作为CA IX抑制剂的潜在功效。总之，源自[具体来源未提及]的香豆素是作为有效CA IX抑制剂的有前景的候选物。
