由于其高死亡率和复杂的治疗策略,癌症构成了重大的全球健康挑战。亚甲基四氢叶酸脱氢酶2(MTHFD2),在各种恶性肿瘤中明显过度表达,代表了抗癌药物开发的有希望的目标。呋喃吡酮A,从内生真菌Arthriniumsp.中分离出的一种新的4-羟基-2-吡啶酮生物碱。GZWMJZ-606已显示出对几种癌细胞系的有效抑制活性。这项研究提供了呋喃吡酮A的第一个计算评估,通过分子对接和200ns分子动力学(MD)模拟,重点研究其对MTHFD2的潜在抑制作用。分子对接显示呋喃吡酮A的结合自由能为-8.08kcal/mol,与对照化合物DS44960156(-8.13kcal/mol)相当,表明与MTHFD2活性位点的稳定相互作用。MD模拟证实了呋喃吡酮A-MTHFD2复合物的结构稳定性,RMSD值范围为1.5至2.9,RMSF值低于4,回转半径(Rg)为26.7µ。呋喃吡酮A在整个模拟中保持大约四个一致的氢键。在0ns处分析呋喃吡酮A的结合姿势取向和与MTHFD2酶的相互作用,40ns,80ns,120ns,160ns,和200ns显示一致和稳定的结合。MM-PBSA分析显示结合自由能(ΔGbind)为-23.57±0.13kcal/mol,静电和范德华相互作用的贡献很大,表明与对照化合物的竞争性结合亲和力(-25.32±0.11kcal/mol)。单个氨基酸残基的贡献,包括关键残基如ARG43,TYR84,ASN87,LYS88,GLN132和PRO314,表明支持呋喃吡酮A-MTHFD2复合物稳定性的强相互作用。ADMET预测表明,呋喃吡酮A符合关键的药物相似性标准,并表现出良好的口服生物利用度,合适的分布剖面,药物-药物相互作用的最小风险,高效消除,和低毒性潜力。这些发现表明,呋喃吡酮A是癌症治疗的有希望的候选者,保证进一步的体外和体内验证,并强调其对新抗癌疗法开发的潜在影响。
Cancer poses a significant global health challenge due to its high mortality rate and complex treatment strategies. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), which is notably overexpressed in various malignancies, represents a promising target for anticancer drug development. Furanpydone A, a new 4-hydroxy-2-pyridone alkaloid isolated from the endophytic fungus Arthrinium sp. GZWMJZ-606, has shown potent inhibitory activity against several cancer cell lines. This study provides the first computational evaluation of furanpydone A, focusing on its potential inhibition of MTHFD2 through molecular docking and 200 ns molecular dynamics (MD) simulations. Molecular docking revealed a binding free energy of -8.08 kcal/mol for furanpydone A, comparable to the control compound DS44960156 (-8.13 kcal/mol), indicating stable interactions with the MTHFD2 active site. MD simulations confirmed the structural stability of the furanpydone A-MTHFD2 complex, with RMSD values ranging from 1.5 to 2.9 Å, RMSF values below 4 Å, and a radius of gyration (Rg) of 26.7 Å. Furanpydone A maintained approximately four consistent hydrogen bonds throughout the simulation. Analysis of furanpydone A binding pose orientations and interactions with the MTHFD2 enzyme at 0 ns, 40 ns, 80 ns, 120 ns, 160 ns, and 200 ns revealed consistent and stable binding. MM-PBSA analysis showed a binding free energy (ΔGbind) of -23.57 ± 0.13 kcal/mol, with electrostatic and van der Waals interactions contributing significantly, suggesting competitive binding affinity to the control compound (-25.32 ± 0.11 kcal/mol). The contribution of individual amino acid residues, including key residues such as ARG43, TYR84, ASN87, LYS88, GLN132, and PRO314, indicated strong interactions that support the stability of the furanpydone A-MTHFD2 complex. ADMET predictions indicated that furanpydone A met key drug-likeness criteria and demonstrated good oral bioavailability, suitable distribution profile, minimal risk of drug-drug interactions, efficient elimination, and low toxicity potential. These findings suggest that furanpydone A is a promising candidate for cancer treatment, warranting further in vitro and in vivo validation, and highlighting its potential impact on the development of new anticancer therapies.