Abstract：
Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP\'s intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARβ interaction were identified, guiding the definition of AFP\'s active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARβ complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib\'s stability with AFP. The study suggests Lapatinib\'s potential in disrupting the AFP-RARβ complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.
摘要：
甲胎蛋白(AFP)是一种主要在胚胎发育过程中表达的糖蛋白。产后水平下降。AFP水平升高与肝纤维化等病理状况相关，肝硬化,和肝细胞癌（HCC）。最近的研究强调了AFP在肝癌进展中的细胞内作用，其中它与磷酸酶和张力蛋白同源物（PTEN）等蛋白质形成复合物，胱天蛋白酶3(CASP3),和视黄酸受体和类视黄醇X受体（RAR/RXR）。RAR和RXR调节与正常生理学中的细胞死亡和肿瘤发生相关的基因表达。AFP阻碍RAR/RXR二聚化，核易位,和功能，促进基因表达有利于HCC的癌症进展，这促使我们将AFP作为候选药物。尽管进行了广泛的研究,靶向AFP以破坏复合物形成和活性的抑制剂仍然很少。在这项研究中,采用蛋白质-蛋白质对接，鉴定了参与AFP-RARβ相互作用的氨基酸残基，指导AFP活性位点的定义，用于潜在的抑制剂筛选。目前,激酶抑制剂在癌症治疗中起重要作用，本研究探讨了重新利用FDA批准的蛋白激酶抑制剂靶向AFP的潜力.与激酶抑制剂的分子对接显示拉帕替尼是AFP-RARβ复合物的候选药物。分子动力学模拟和结合能计算，采用力学/泊松-玻尔兹曼表面积(MM-PBSA)，证实拉帕替尼与AFP的稳定性。该研究表明，拉帕替尼具有破坏AFP-RARβ复合物的潜力，为治疗分子分层AFP阳性HCC或其早期阶段提供了有希望的途径。
