Investigating the multitargeted anti-diabetic potential of cucurbitane-type triterpenoid from <i>Momordica charantia</i>: an LC-MS, docking-based MM\GBSA and MD simulation study

Type 2 diabetes accounts for the largest percentage of all diabetic cases worldwide. Cucurbitane-type triterpenes are mainly found in <i>Momordica charantia</i> and possess excellent pharmacological activities. This study was designed to identify cucurbitane-type triterpene from <i>Momordica charantia</i> using Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, examine its anti-diabetic property with molecular docking against diabetes enzymes (alpha-amylase, alpha-glucosidase, dipeptidyl dipeptidase IV and peroxisome proliferator-activated receptor gamma). The stability and interactions of the docked complexes were investigated using molecular dynamics simulation, while the pharmacokinetic and toxicity profile of the ligand was examined using an ADMET server. (23E)-Cucurbita-5,23,25-triene-3,7-dione (CUB) was identified from the LC-MS profiling of the methanolic extract of <i>M. charantia</i>. The molecular docking studies showed that the identified phytochemical elicited good binding energy against all the target receptors. The RMSD and RMSF plots obtained from the 100 ns molecular dynamics simulation showed that the ligand was stable and established substantial interactions with the amino acid residues of the diabetes enzymes which were confirmed by the MM\GBSA computations. The pharmacokinetic and toxicity properties of the ligand showed it was safer as an anti-diabetic drug candidate. Extensive isolation, <i>in vitro</i> and <i>in vivo</i> studies of the ligand against the diabetic enzymes is recommended.

2型糖尿病占全球糖尿病总病例的最大比例。葫芦烷型三萜（Cucurbitane-type triterpenes）主要存在于苦瓜（Momordica charantia）中，且具备优异的药理活性。本研究旨在通过液相色谱-质谱联用法（Liquid Chromatography-Mass Spectrometry，LC-MS）从苦瓜中鉴定葫芦烷型三萜类成分，并通过针对糖尿病相关酶（α-淀粉酶、α-葡萄糖苷酶、二肽基肽酶IV与过氧化物酶体增殖物激活受体γ）的分子对接（molecular docking）实验，评估其抗糖尿病活性。本研究通过分子动力学模拟（molecular dynamics simulation）探究了对接复合物的稳定性与相互作用模式，并借助ADMET服务器（ADMET server）分析了该配体（ligand）的药代动力学与毒性特征。研究人员从苦瓜的甲醇提取物的LC-MS图谱分析中，鉴定出了(23E)-葫芦烷-5,23,25-三烯-3,7-二酮（CUB）。分子对接实验结果显示，该鉴定得到的植物化学成分对所有靶标受体均表现出良好的结合能。通过100纳秒分子动力学模拟得到的均方根偏差（Root Mean Square Deviation，RMSD）与均方根波动（Root Mean Square Fluctuation，RMSF）图谱显示，该配体稳定性良好，且可与糖尿病相关酶的氨基酸残基形成稳定的相互作用，这一结果通过MM/GBSA计算（MMGBSA computations）得到了验证。该配体的药代动力学与毒性特征分析结果表明，其作为抗糖尿病候选药物具有较高的安全性。建议针对该配体开展大规模分离纯化以及针对糖尿病相关酶的体外（in vitro）与体内（in vivo）实验研究。