Background: Hepatocellular carcinomas (HCCs) are inherently chemotherapy-resistant tumors with about 30-50% activation of PI3K/Akt/mTOR pathway, and this pathway is not aberrant in normal cells. Therefore, targeting the PI3K/Akt/mTOR pathway has become a promising strategy in drug designing to combat liver cancer. Recently, many studies with phytochemicals suggest few classes of compounds, especially flavonoids, to be useful in down-regulating the PI3K/Akt/mTOR pathway corresponding to HCC. In the present study, an attempt is made to explore flavonoids, from which the best mTORC1 inhibitor against hepatocellular carcinoma is selected using computational molecular modeling.

Methods: In the present study, we performed a virtual screening method with phytochemicals of flavonoid category. To ensure proper bioavailability and druggability, pharmacokinetic and interaction parameters have been used to screen the molecules. The target protein molecules have been selected from the RCSB. The interaction studies have been conducted using Biovia Discovery Studio client version 17.2.0.1.16347 and the pharmacokinetic predictions have been made through ADMET SAR. The responsiveness towards the regulation of the mTOR pathway varies from person to person, demanding a pharmacogenomic approach in the analysis. The genetic variants (Single Nucleotide Variants-SNVs) corresponding to the mutations have been identified.

Results and Discussions: The study identified phytoconstituents with better interaction with receptor FKBP12, a Rapamycin binding domain which is the target of Rapamycin and its analogues for mTORC1 inhibition in HCC. Another protein, ‘AKT serine/threonine-protein kinase’ has been identified, which is associated with activation of mTORC1. The molecular interaction studies (docking studies) and ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to identify the affinity between selected phytoconstituents as mTORC1 inhibitor against Hepatocellular carcinoma. The docking studies support Kaempferol to be a potential ligand with docking score values of 33.4 (3CQU-3D structure of AKT1)] and 27.3 (2FAP-3D structure of FRB domain of mTOR) respectively as compared to that of standard drug Everolimus with 24.4 (3CQU-3D structure of AKT1) and 20.1 (2FAP-3D structure of FRB domain of mTOR) respectively. Docking studies along with ADMET results show that Kaempferol has favorable drug likeliness properties and binds to the same active site (site1) of the targeted proteins (3CQU-3D structure of AKT1) and (2FAP-3D structure of FRB domain of mTOR) where the standard drug Everolimus is known to bind.

Conclusion: The study exhibited that Kaempferol had a better binding affinity towards the receptor FKBP12, a Rapamycin Binding Domain and AKT serine/threonine-protein kinase resulting in its better efficacy in the mTORC1 inhibition as when compared with standard drug Everolimus against HCC. To the best of our knowledge, no studies have been reported on Kaempferol as mTORC1 inhibitor against Hepatocellular carcinoma.

背景：肝细胞癌（HCC）本质上是化学疗法耐药的肿瘤，其PI3K / Akt / mTOR途径的激活率约为30-50％，在正常细胞中该途径并不异常。因此，靶向PI3K / Akt / mTOR途径已成为对抗肝癌的药物设计中一种有前途的策略。最近，许多有关植物化学物质的研究表明，很少有几类化合物（尤其是类黄酮）可用于下调对应于HCC的PI3K / Akt / mTOR途径。在本研究中，人们试图探索黄酮类化合物，使用计算分子模型从中选择最佳的针对肝细胞癌的mTORC1抑制剂。

方法：在本研究中，我们使用类黄酮类植物化学物质进行了虚拟筛选。为了确保适当的生物利用度和药物可及性，已使用药代动力学和相互作用参数筛选分子。靶蛋白分子已选自RCSB。使用Biovia Discovery Studio客户端版本17.2.0.1.16347进行了相互作用研究，并通过ADMET SAR进行了药代动力学预测。对mTOR途径调控的反应因人而异，需要在分析中采用药物基因组学方法。已经鉴定出与突变相对应的遗传变异（单核苷酸变异-SNV）。

结果与讨论：该研究确定了与受体FKBP12相互作用更好的植物成分，该受体是雷帕霉素结合域，是雷帕霉素及其类似物在肝癌中抑制mTORC1的靶标。已经鉴定出另一种蛋白“ AKT丝氨酸/苏氨酸蛋白激酶”，它与mTORC1的激活有关。分子相互作用研究（对接研究）和ADMET（吸收，分布，代谢，排泄和毒性）分析用于鉴定作为mTORC1肝细胞癌抑制剂的所选植物成分之间的亲和力。与标准药物依维莫司（Everolimus）的对接得分分别为33.4（AKT1的3CQU-3D结构）和27.3（mTOR的FRB结构域的2FAP-3D结构）的对接研究支持山Ka酚为潜在配体。4（AKT1的3CQU-3D结构）和20.1（mTOR的FRB域的2FAP-3D结构）。对接研究以及ADMET结果表明，Kaempferol具有良好的药物相似性，并与靶蛋白（AKT1的3CQU-3D结构）和（mTOR的FRB结构域的2FAP-3D结构）的相同活性位点（site1）结合，已知标准药物依维莫司可以结合。

结论：该研究表明山emp酚对受体FKBP12，雷帕霉素结合域和AKT丝氨酸/苏氨酸-蛋白激酶具有更好的结合亲和力，与标准药物依维莫司抗HCC相比，其对mTORC1的抑制作用更好。据我们所知，尚无关于山emp酚作为抗肝细胞癌mTORC1抑制剂的研究报道。