Rao Vyshnavi Vishwanadham, Shanti Koppala Narayanappa
Department of Chemistry, MES College of Arts, Science and Commerce, Bengaluru 560003, India; Department of Biotechnology, PES University, Bengaluru 560085, India.
Department of Biotechnology, PES University, Bengaluru 560085, India.
J Mol Graph Model. 2025 May;136:108938. doi: 10.1016/j.jmgm.2024.108938. Epub 2025 Jan 1.
Diabetes mellitus, characterized by persistent hyperglycemia, remains a critical global health challenge. Inhibition of human pancreatic alpha-amylase, a key enzyme catalyzing carbohydrate digestion, is a promising approach to manage postprandial glucose levels. Cinnamomum zeylanicum, a medicinal plant known for its therapeutic potential, harbors bioactive compounds that can act as natural alpha-amylase inhibitors, though their mechanisms remain underexplored. In this study, molecular docking and 200 ns molecular dynamics (MD) simulations were employed to evaluate the inhibitory potential of 18 phytochemicals derived from Cinnamomum zeylanicum. Two lead compounds, 1HE (1,2,4a,5,6,8a-Hexahydro-1-isopropyl-4,7-dimethylnaphthalene) and C4B (cis-4-Benzyl-2,6-diphenyl-tetrahydropyran), exhibited superior binding affinities (-7.91 and -8.78 kcal/mol, respectively) compared to the FDA-approved inhibitors, acarbose (-8.2 kcal/mol) and miglitol (-5.6 kcal/mol). MD simulations confirmed the stability of the complexes, with RMSD values of 0.21 ± 0.02 nm for 1HE and 0.24 ± 0.03 nm for C4B, showing minimal structural deviations. Structural analyses, including radius of gyration (Rg) and solvent-accessible surface area (SASA), revealed stable and compact protein-ligand conformations. Notably, free energy landscape (FEL) analysis indicated that C4B induces multiple metastable states, suggesting a dynamic inhibitory mechanism potentially involving allosteric regulation. These results highlight 1HE and C4B as promising natural inhibitors with favorable stability, binding characteristics, and inhibitory mechanisms. Further in vitro and in vivo studies are warranted to validate their therapeutic potential as safe and effective alternatives for diabetes management.
糖尿病以持续性高血糖为特征，仍然是一项严峻的全球健康挑战。抑制人胰腺α-淀粉酶（一种催化碳水化合物消化的关键酶）是控制餐后血糖水平的一种有前景的方法。锡兰肉桂是一种具有治疗潜力的药用植物，含有可作为天然α-淀粉酶抑制剂的生物活性化合物，但其作用机制仍未得到充分研究。在本研究中，采用分子对接和200纳秒分子动力学（MD）模拟来评估从锡兰肉桂中提取的18种植物化学物质的抑制潜力。两种先导化合物，1HE（1,2,4a,5,6,8a-六氢-1-异丙基-4,7-二甲基萘）和C4B（顺式-4-苄基-2,6-二苯基-四氢吡喃），与美国食品药品监督管理局（FDA）批准的抑制剂阿卡波糖（-8.2 kcal/mol）和米格列醇（-5.6 kcal/mol）相比，表现出更高的结合亲和力（分别为-7.91和-8.78 kcal/mol）。MD模拟证实了复合物的稳定性，1HE的均方根偏差（RMSD）值为0.21±0.02 nm，C4B的为0.24±0.03 nm，显示出最小的结构偏差。包括回转半径（Rg）和溶剂可及表面积（SASA）在内的结构分析揭示了稳定且紧凑的蛋白质-配体构象。值得注意的是，自由能景观（FEL）分析表明C4B诱导了多个亚稳态，这表明其可能存在涉及变构调节的动态抑制机制。这些结果突出了1HE和C4B作为有前景的天然抑制剂，具有良好的稳定性、结合特性和抑制机制。有必要进行进一步的体外和体内研究，以验证它们作为糖尿病管理安全有效替代方案的治疗潜力。
