靶点蛋白结构与药物分子对接的计算机虚拟筛选法的一次接力赛
这是靶点蛋白结构与药物分子对接的计算机虚拟筛选法的又一研究新成果，对肠癌的治疗有非常重要的意义。APC突变，肠癌三巨头之首。APC突变目前有药在研，但还没有上市。2013年的一篇论文和2021年的一篇论文，以某种程度上的接力赛方式，通过两次模型计算和筛选，先是筛选出CK1ε是治疗APC突变的关键靶点，然后又筛选出依曲韦林是CK1ε抑制剂的替代药物。
一、apc突变会造成 wnt/β-catenin 通路的激活；apc突变对β-catenin的激活依赖于APC在第一个20个氨基酸重复处的磷酸化，而该位点的磷酸化是由CK1ε介导的。
“We find that the phosphorylated truncated form of APC can outcompete Axin for binding to β-catenin, provided that Axin is limiting, and thereby sequester β-catenin away from Axin and the Axin-recruited kinases CK1α and GSK -3β. Full-length APC also competes with Axin for binding to β-catenin; however, full-length APC is able, through its SAMP repeats, which bind Axin and which are missing in truncated oncogenic forms of APC, to bring β-catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on β-catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by CK1ε, we suggest that CK1ε is a potential target for therapeutic intervention in colorectal cancer. Specific inhibition of CK1ε is predicted to limit binding of β-catenin to truncated APC and thereby to reverse the effect of APC truncation.” （《Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells》）
二、依曲韦林对CK1ε有高度结合亲和力，能形成稳定的复合物，是CK1ε抑制剂的候选药物
“CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.” （《Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening》）
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