RNA结合蛋白LIN28(人异常细胞谱系28)和miRNALet-7(致死7)的相互抑制被认为在肝细胞癌(HCC)中具有主要作用。虽然靶向这种抑制相互作用对治疗有效,它会对葡萄糖代谢产生其他不利影响,并增加胰岛素抵抗。因此,本研究旨在确定靶向Lin28/let-7相互作用的小分子以及提高胰岛素敏感性的额外效力.通过高通量虚拟筛选筛选的22,14,996个小分子,6个分子,即41354,1558,12437,23837,15710和8319能够阻断LIN28与let-7的相互作用,并通过与PPARγ(过氧化物酶体增殖物激活受体γ)的相互作用增加胰岛素敏感性.MM-GBSA(分子力学-广义玻恩表面积)分析用于重新评分对接复合物的结合亲和力。经进一步分析,还可以看出,这些分子具有优异的ADME(吸收,Distribution,代谢,和排泄)的性质,并在生物模拟环境(分子动力学模拟)中与目标形成稳定的复合物,持续100ns。从我们的结果来看,我们假设这些鉴定的6个小分子可能是HCC治疗和由HCC治疗引起的葡萄糖代谢紊乱的潜在候选者。
The reciprocal suppression of an RNA-binding protein LIN28 (human abnormal cell lineage 28) and miRNA Let-7 (Lethal 7) is considered to have a prime role in hepatocellular carcinoma (HCC). Though targeting this inhibition interaction is effective for therapeutics, it causes other unfavorable effects on glucose metabolism and increased insulin resistance. Hence, this study aims to identify small molecules targeting Lin28/let-7 interaction along with additional potency to improve insulin sensitivity. Of 22,14,996 small molecules screened by high throughput virtual screening, 6 molecules, namely 41354, 1558, 12437, 23837, 15710, and 8319 were able to block the LIN28 interaction with let-7 and increase the insulin sensitivity via interacting with PPARγ (peroxisome proliferator-activated receptors γ). MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) analysis is used to re-score the binding affinity of docked complexes. Upon further analysis, it is also seen that these molecules have superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties and form stable complexes with the targets for a significant period in a biologically simulated environment (Molecular Dynamics simulation) for 100 ns. From our results, we hypothesize that these identified 6 small molecules can be potential candidates for HCC treatment and the glucose metabolic disorder caused by the HCC treatment.