Abstract：
Focal adhesion kinase (FAK) is an enzyme of paramount importance as it is involved in several critical roles, which are linked to proliferation of cancer cells. FAK is quintessential for cancer cell mitigation, adhesion and survival, downregulation of which interferes with the growth of cancer cells. The expression of FAK is elevated in breast cancer, hepatocellular carcinomas, neuroblastoma cells, demonstrating the need for FAK inhibitors as a potential treatment. Based on an in silico drug screen, the study aimed to identify potential FAK inhibitors. 3180 molecules retrieved from the Zinc database comprising biogenic molecules, FDA-approved drugs and compounds in clinical trials were screened against the FAK enzyme (PDB:2ETM). The XP docking study of the best 51 ligands revealed that ZINC02033589 (Silymarin) showed good binding to FAK with -10.97 kcal/mol dock score followed by ZINC00518397 with -8.23 kcal/mol and ZINC03831112 - 8.07 kcal/mol. The interactions of the top three ligands with FAK were further validated by molecular dynamic simulation study of 100 ns and MM-GBSA calculations. The ΔG of binding of ZINC02033589, ZINC00518397 and ZINC03831112 was found to be -59.09, -45.08 and -48.53 kcal/mol respectively. The study established the fact that among the three molecules, ZINC02033589 showed good stability and binding towards FAK. These results could usher in the development of potential FAK inhibitor entities, that could be persuaded and substantiated by the molecules identified in this study for subsequent synthetic and bioactivity research studies.Communicated by Ramaswamy H. Sarma.
摘要：
粘着斑激酶（FAK）是一种至关重要的酶，因为它参与了几个关键作用，这与癌细胞的增殖有关。FAK是癌细胞缓解的典范，粘附和存活，其下调会干扰癌细胞的生长。乳腺癌中FAK的表达升高,肝细胞癌，神经母细胞瘤细胞，证明需要FAK抑制剂作为潜在的治疗方法。根据电脑药物筛选，该研究旨在鉴定潜在的FAK抑制剂。从锌数据库检索的3180个分子，包括生物分子，针对FAK酶(PDB:2ETM)筛选了FDA批准的药物和临床试验中的化合物。最佳51配体的XP对接研究表明，ZINC02033589（水飞蓟素）与FAK的结合良好，对接评分为-10.97kcal/mol，其次是ZINC00518397，-8.23kcal/mol和ZINC03831112-8.07kcal/mol。通过100ns的分子动力学模拟研究和MM-GBSA计算进一步验证了前三种配体与FAK的相互作用。发现ZINC02033589，ZINC00518397和ZINC03831112的结合ΔG分别为-59.09，-45.08和-48.53kcal/mol。这项研究证实了这三种分子中，ZINC02033589显示良好的稳定性和对FAK的结合。这些结果可能会导致潜在的FAK抑制剂实体的发展，这可以通过本研究中确定的分子说服和证实，用于随后的合成和生物活性研究。由RamaswamyH.Sarma沟通。
