Rahman M Oliur, Ahmed Sheikh Sunzid, Alqahtani Ali S, Hamid Kaiser, Sultana Maria, Ali Mohammad Ajmal
Department of Botany, Faculty of Biological Sciences, University of Dhaka, Dhaka, 1000, Bangladesh.
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
Appl Biochem Biotechnol. 2025 May;197(5):3215-3257. doi: 10.1007/s12010-024-05160-6. Epub 2025 Jan 21.
Diabetes affects approximately 422 million people worldwide, leading to 1.5 million deaths annually and causing severe complications such as kidney failure, neuropathy, and cardiovascular disease. Aldose reductase (AR), a key enzyme in the polyol pathway, is an important therapeutic target for managing these complications. The high cost, severe side effects, and rising drug resistance in traditional diabetes treatments underscore the urgent need for novel AR-targeting antidiabetic agents. Ficus benjamina used in traditional medicine demonstrates promising potential for diabetes management. This study investigated the antidiabetic potential of F. benjamina phytocompounds targeting AR receptor employing a structure-based drug design approach to identify potential antidiabetic drug agents. Using molecular docking, ADMET analysis, molecular dynamics (MD) simulation, MM/GBSA, MM/PBSA, and DFT calculations, we identified three promising lead compounds: adenocarpine (- 9.2 kcal/mol), marmesin (- 8.8 kcal/mol), and lycocernuine (- 8.4 kcal/mol). These compounds presented favorable pharmacokinetic, pharmacodynamic, and toxicity profiles, with a 500-ns MD simulation confirming their stability, supported by PCA and Gibbs FEL analysis. MM/GBSA study identified adenocarpine (- 72.53 kcal/mol) as the best compound, outperforming marmesin (- 70 kcal/mol) and lycocernuine (- 61.95 kcal/mol). DFT analysis revealed that adenocarpine exhibited the highest molecular reactivity (3.914 eV), while lycocernuine demonstrated the greatest kinetic stability (6.377 eV). Marmesin and lycocernuine showed increased reactivity upon transitioning from the free states (4.441 eV and 6.377 eV, respectively) to the bound states (4.359 eV and 6.231 eV, respectively). These results could lead to the development of adenocarpine, marmesin, and lycocernuine as novel drug candidates for diabetes, warranting further in vitro and in vivo validation.
糖尿病影响着全球约4.22亿人，每年导致150万人死亡，并引发严重并发症，如肾衰竭、神经病变和心血管疾病。醛糖还原酶（AR）是多元醇途径中的关键酶，是控制这些并发症的重要治疗靶点。传统糖尿病治疗方法成本高昂、副作用严重且耐药性不断上升，这凸显了对新型AR靶向抗糖尿病药物的迫切需求。传统医学中使用的垂叶榕在糖尿病管理方面显示出有前景的潜力。本研究采用基于结构的药物设计方法，研究垂叶榕植物化合物靶向AR受体的抗糖尿病潜力，以识别潜在的抗糖尿病药物。通过分子对接、ADMET分析、分子动力学（MD）模拟、MM/GBSA、MM/PBSA和DFT计算，我们确定了三种有前景的先导化合物：腺荚豆碱（-9.2千卡/摩尔）、豆甾醇（-8.8千卡/摩尔）和石蒜碱（-8.4千卡/摩尔）。这些化合物呈现出良好的药代动力学、药效学和毒性特征，500纳秒的MD模拟证实了它们的稳定性，主成分分析（PCA）和吉布斯自由能景观（Gibbs FEL）分析也提供了支持。MM/GBSA研究确定腺荚豆碱（-72.53千卡/摩尔）是最佳化合物，优于豆甾醇（-70千卡/摩尔）和石蒜碱（-61.95千卡/摩尔）。DFT分析表明，腺荚豆碱表现出最高的分子反应性（3.914电子伏特），而石蒜碱表现出最大的动力学稳定性（6.377电子伏特）。豆甾醇和石蒜碱从游离态（分别为4.441电子伏特和6.377电子伏特）转变为结合态（分别为4.359电子伏特和6.231电子伏特）时，反应性增加。这些结果可能会促使腺荚豆碱、豆甾醇和石蒜碱开发成为新型糖尿病候选药物，值得进一步进行体外和体内验证。
