脂肪酸合酶(FASN)是一种脂质代谢蛋白,其通过从头脂肪生成为癌细胞提供必需的营养。此外,它在其他疾病中起着关键作用,包括肥胖和炎症。因此,靶向FASN蛋白的β-酮酰还原酶(KR)结构域,我们对一些选择性的生物活性天然分子进行了计算机模拟研究,并采用了再利用策略来鉴定FASN抑制剂.接下来是吸收的分子对接研究,Distribution,代谢和排泄(ADME)预测,结合自由能计算,使用薛定谔药物发现软件对FASN蛋白(PDBID:6NNA)进行分子动力学(MD)模拟。化合物芦丁,反式绿原酸,norbergenin,杨梅素,槲皮素,physalolactone,槲皮素-3-O-半乳糖苷,山奈酚,asperulosidic酸,木犀草素,姜黄素,12-脱氧黄芪甲酚,脚掌,Herndifoline,并且没有淀粉样蛋白E被确定为命中,表现出更好的对接分数(分别为-16.2,-14.1,-12.3,-12.1,-12.0,-11.3,-10.3,-9.8,-9.3,-9.2,-9.1,-8.5,-8.4,-8.3,-7.9)以及与FASNKR域的Ser2021和Tyr2034氨基酸的氢键相互作用。与蛋白质6NNA复合物的前五名命中的MD模拟研究揭示了导致配体稳定的显着相互作用,均方根偏差(RMSD)低于5.00,并通过评估均方根波动进一步验证了稳定性,溶剂可及表面积,和回转半径图。此外,当使用基于HPLC的高效液相色谱法对MCF-7细胞中的棕榈酸进行评估时,前四个命中(50µM)的FASN抑制作用>50%。因此,芦丁,反式绿原酸,norbergenin,和杨梅素被认为是前瞻性的FASN抑制导线。总的来说,结果提供了对药效特征的有益修饰,可以提高抑制作用.由RamaswamyH.Sarma沟通。
Fatty acid synthase (FASN) enzyme is a lipid metabolism protein that provides the essential nutrients to cancer cells through de novo lipogenesis. Also, it plays a key role in other disease conditions, including obesity and inflammation. Hence, targeting the β-ketoacyl reductase (KR) domain of FASN protein, an in-silico
study was performed on some selective bioactive natural molecules following a repurposing strategy to identify FASN inhibitors. A molecular docking
study followed by Absorption, Distribution, Metabolism and Excretion (ADME) predictions, binding free energy calculations, and molecular dynamics (MD) simulations were performed against FASN protein (PDB ID:6NNA) using Schrodinger Drug Discovery Software. Compounds rutin, trans-chlorogenic acid, norbergenin, myricetin, quercetin, physalolactone, quercetin-3-O-galactoside, kaempferol, asperulosidic acid, luteolin, curcumin, 12-deoxywithastramonolide, pedunculoside, hernandifoline, and withafastuosin E were identified as hits, presenting better docking scores (-16.2, -14.1, -12.3, -12.1, -12.0, -11.3, -10.3, -9.8, -9.3, -9.2, -9.1, -8.5, -8.4, -8.3, -7.9, respectively) and hydrogen bond interactions with Ser 2021 and Tyr 2034 amino acids of the KR domain of FASN. The MD simulations
study of top five hits in complex with protein 6NNA uncovered the significant interactions leading to the stabilization of ligand with Root Mean Square Deviation (RMSD) below 5.00 Å and the stability was further validated by evaluating the root mean square fluctuation, solvent accessible surface area, and radius of gyration graphs. Also, the FASN inhibition effect of top four hits (50 µM) was >50% when corroborated using High Performance Liquid Chromatography HPLC-based estimation of palmitic acid in MCF-7 cells. Thus rutin, trans-chlorogenic acid, norbergenin, and myricetin are proposed as prospective FASN inhibitory leads. Overall, the results provided useful modifications in pharmacophoric features that could improve the inhibitory effect.Communicated by Ramaswamy H. Sarma.