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TRAF2 and NCK-interacting kinase inhibitors for colorectal cancer; in vitro and theoretical validations.
ACS Combinatorial Science ( IF 3.903 ) Pub Date : 2020-09-22 , DOI: 10.1021/acscombsci.0c00027
Sherlin Rosita Arokiaraj 1 , Nargis Begum Tajuddin 1 , Karthikeyan Muthusamy 2 , John Marshal Jayaraj 2 , Manikandan Alagumuthu 3
Affiliation  

TRAF2 and NCK-interacting kinase (TNIK) is a critical factor in colorectal cancer (CRC) proliferation mediated by Wnt signaling. We attempted to identify efficient TNIK inhibitors using computational high-throughput virtual screening (HTVS) from various drug banks and databases. By performing/on performing e-pharmacophore screening and molecular docking methods, from ∼700 000 molecules, compounds LC_222150, LC_112060, and LC_64796 were identified as potential leads, through molecular dynamics (MD) simulations and density functional theory (DFT). These top 3 structures were commercially procured, and their inhibitory activity was assessed in vitro. Significant TNIK inhibition was observed, with an average IC50 of 18.33 ± 0.75 nM. In terms of anticancer activity, the observed average relative % activity (RPA) of 90.28 ± 1.04 for these compounds compared well with doxorubicin (86.75 ± 1.45) as a standard. Compounds LC_222150, LC_112060, and LC_64796, therefore, warrant further evaluation in vivo to assess their CRC therapeutic effects.

中文翻译:

用于结直肠癌的 TRAF2 和 NCK 相互作用激酶抑制剂;体外和理论验证。

TRAF2 和 NCK 相互作用激酶 (TNIK) 是Wnt信号介导的结直肠癌 (CRC) 增殖的关键因素。我们尝试使用来自各种药物库和数据库的计算高通量虚拟筛选 (HTVS) 来识别有效的 TNIK 抑制剂。通过执行/继续执行电子药效团筛选和分子对接方法,通过分子动力学 (MD) 模拟和密度泛函理论 (DFT),从大约 700 000 个分子中,化合物 LC_222150、LC_112060 和 LC_64796 被确定为潜在先导物。这些前 3 种结构是商业采购的,并在体外评估了它们的抑制活性。观察到显着的 TNIK 抑制,平均 IC 5018.33 ± 0.75 nM。在抗癌活性方面,观察到的这些化合物的平均相对活性 (RPA) 为 90.28 ± 1.04,与作为标准的多柔比星 (86.75 ± 1.45) 相比非常好。因此,化合物 LC_222150、LC_112060 和 LC_64796 需要在体内进行进一步评估,以评估它们的 CRC 治疗效果。
更新日期:2020-11-09
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