Unveiling a novel ellagic acid derivative as a potent lipoxygenase (LOX) inhibitor: integration of computational modeling and experimental validation.

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wali Ullah, Ghias Uddin, Abdur Rauf, Muhammad Umer Khan, Zuneera Akram, Chaudhry Ahmed Shabbir, Abdulhakeem S Alamri, Walaa F Alsanie, Marcello Iriti
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引用次数: 0

Abstract

Cornus macrophylla has been traditionally recognized for its medicinal properties, particularly in managing inflammatory conditions. However, a scientific understanding of its bioactive constituents and mechanisms remains underexplored. This study aimed to isolate and characterize bioactive compounds from the bark of C. macrophylla and evaluate their anti-inflammatory potential through in silico and in vitro analyses. A total of ten compounds, including an ellagic acid derivative and nine steroids and triterpenes, were isolated. Comprehensive analyses integrating molecular docking, ADMET profiling, and density functional theory (DFT) calculations were conducted to elucidate the molecular and anti-inflammatory properties. Experimental validation was performed to confirm the findings. 1,2,3-trimethoxychromeno[5,4,3-cde][1,3]dioxolo[4,5-h]chromene-5,11-dione (1) emerged as the most active compound among those tested, demonstrating moderate inhibition of lipoxygenase (LOX), exhibiting an IC50 value of 78.1 ± 0.03 µM. It also exhibited measurable suppression of respiratory burst activity in human neutrophils, achieving an IC50 of 298.21 ± 0.037 µM, comparable to the benchmark anti-inflammatory agent, Indomethacin (IC50: 271.14 ± 0.032 µM). Molecular docking studies revealed that compound 1, strongly interacts with 15-LOX, demonstrating a binding affinity of -7.038 kcal/mol and forming stable interactions with key active site residues. ADMET profiling and DFT analysis indicated its favourable drug-like properties, reinforcing its potential as a therapeutic candidate. The findings highlight compound (1) as a potent natural inhibitor of LOX, with significant anti-inflammatory activity validated through both experimental and computational approaches. Its efficacy and drug-likeness underscore its therapeutic potential for developing novel anti-inflammatory agents. Further studies are warranted to explore its clinical applicability.

揭示一种新的鞣花酸衍生物作为一种有效的脂氧合酶(LOX)抑制剂:计算模型和实验验证的集成。
大叶茱萸传统上被认为具有药用价值,特别是在治疗炎症方面。然而,对其生物活性成分和机制的科学理解仍未得到充分探索。本研究旨在从巨叶假树皮中分离和鉴定活性化合物,并通过体内和体外分析评价其抗炎活性。共分离得到10个化合物,包括一个鞣花酸衍生物和9个甾体和三萜。结合分子对接、ADMET谱分析和密度泛函理论(DFT)计算进行综合分析,以阐明其分子和抗炎特性。进行了实验验证以证实研究结果。1,2,3-三甲氧基chromeno[5,4,3-cde][1,3]dioxolo[4,5-h]chromene-5,11-dione(1)是测试中活性最高的化合物,表现出适度的脂氧合酶(LOX)抑制作用,IC50值为78.1±0.03µM。它对人中性粒细胞的呼吸爆发活性也有明显的抑制作用,IC50为298.21±0.037µM,与基准抗炎药吲哚美辛(IC50: 271.14±0.032µM)相当。分子对接研究表明,化合物1与15-LOX相互作用强,结合亲和力为-7.038 kcal/mol,与关键活性位点残基形成稳定的相互作用。ADMET分析和DFT分析表明其具有良好的药物样特性,增强了其作为治疗候选药物的潜力。研究结果强调化合物(1)是一种有效的天然LOX抑制剂,通过实验和计算方法验证了其显著的抗炎活性。其疗效和药物相似性强调了其开发新型抗炎药的治疗潜力。其临床适用性有待进一步研究。
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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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