Mohamed Alkhair Adam Khalil, Woasiedem Tamekloe, Appiah-Ofori Philip Collins, Adam Esraa Mohammed Abdulmahmoud, Obiri Samuel Asiamah, Borquaye Lawrence Sheringham, Adokoh Christian K, Elamin Ghazi, Asiamah Isaac
Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana, ucc.edu.gh.
Department of Chemistry, School of Physical Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana, ucc.edu.gh.
Biomed Res Int. 2025 Sep 3;2025:4196295. doi: 10.1155/bmri/4196295. eCollection 2025.
Buruli ulcer (BU), a neglected tropical disease caused by , requires more effective and accessible treatments. Clinical trials have shown the efficacy of herbal formulations containing , , , and , although the active phytochemicals remain unstudied. In the present study, we employed an approach to identify the active phytochemicals from these plants that could inhibit dihydrofolate reductase (DHFR), a crucial enzyme for mycobacterial survival. A library of 172 phytochemicals was screened using molecular docking, followed by 300-ns molecular dynamics (MD) simulations using AMBER for the top hits and standard drugs (methotrexate and trimethoprim). Binding free energies were calculated using the molecular mechanics/generalized born surface area (MM/GBSA) method. The extended MD simulations and post hoc MM/GBSA analysis revealed that kaempferol-3-O-rutinoside ( -51.62 kcal/mol) and neochlorogenic acid (G -49.44 kcal/mol) exhibited the strongest and most stable binding to DHFR. The binding energies were more favorable than both methotrexate ( -44.18 kcal/mol) and trimethoprim ( -41.01 kcal/mol) used as positive controls. Stability analyses (RMSD and RMSF) and principal component analysis (PCA) confirmed that these compounds form stable complexes and induce specific conformational states in the enzyme. Favorable ADMET profiles, particularly the lack of predicted skin sensitization, support their potential for topical use. This study identifies kaempferol-3-O-rutinoside and neochlorogenic acid as the most promising lead candidates for developing novel BU therapies, warranting their prioritization for experimental validation.
布鲁里溃疡（BU）是一种由[具体病原体未给出]引起的被忽视的热带病，需要更有效且可及的治疗方法。临床试验已表明含有[相关植物成分未给出]的草药配方具有疗效，尽管其活性植物化学物质尚未得到研究。在本研究中，我们采用一种[具体方法未给出]来从这些植物中鉴定出能够抑制二氢叶酸还原酶（DHFR）的活性植物化学物质，DHFR是分枝杆菌生存的关键酶。使用分子对接对172种植物化学物质的文库进行筛选，随后对排名靠前的化合物和标准药物（甲氨蝶呤和甲氧苄啶）使用AMBER进行300纳秒的分子动力学（MD）模拟。使用分子力学/广义玻恩表面积（MM/GBSA）方法计算结合自由能。扩展的MD模拟和事后的MM/GBSA分析表明，山奈酚-3-O-芸香糖苷（[结合能数值未给出]-51.62千卡/摩尔）和新绿原酸（G[结合能数值未给出]-49.44千卡/摩尔）与DHFR表现出最强且最稳定的结合。其结合能比用作阳性对照的甲氨蝶呤（[结合能数值未给出]-44.18千卡/摩尔）和甲氧苄啶（[结合能数值未给出]-41.01千卡/摩尔）更有利。稳定性分析（RMSD和RMSF）以及主成分分析（PCA）证实这些化合物形成稳定的复合物并在酶中诱导特定的构象状态。良好的ADMET特性，尤其是缺乏预测的皮肤致敏性，支持它们局部使用的潜力。本研究确定山奈酚-3-O-芸香糖苷和新绿原酸是开发新型布鲁里溃疡疗法最有前景的先导候选物，值得优先进行实验验证。
