Discovery of novel IDH1-R132C inhibitors through structure-based virtual screening.
Discovery of novel IDH1-R132C inhibitors through structure-based virtual screening.
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DOI：
10.3389/fphar.2022.982375
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
异柠檬酸脱氢酶（IDH）属于参与糖代谢的酶家族。它存在于许多生物体中，是突变最多的代谢酶之一。在当前的研究中，我们使用基于对接的虚拟筛选和细胞抑制试验鉴定了新型IDH 1-R132 C抑制剂。从基于对接的虚拟筛选中获得了总共100个具有高对接分数的分子。细胞抑制试验表明，浓度为10 μM的5种化合物可抑制携带IDH 1-R132 C突变的癌细胞增殖> 50%。化合物（T001-0657）显示出对携带IDH 1-R132 C突变的癌细胞的最有效作用，半最大抑制浓度（IC 50）值为1.311 μM。它还显示出对具有野生型IDH 1的癌细胞和正常细胞的细胞毒性作用，IC 50值分别为49.041 μM和>50 μM。进行分子动力学模拟以研究别构抑制剂化合物A和鉴定的化合物T001-0657与IDH 1-R132 C结合的激酶结构结合的稳定性。均方根偏差、均方根波动和结合自由能计算表明，两种化合物均与IDH 1-R132 C紧密结合。总之，本研究中鉴定的化合物对携带IDH 1-R132 C突变的癌细胞具有高选择性，并且可以被认为是进一步开发IDH 1-R132 C抑制剂的有希望的命中化合物。
Isocitrate dehydrogenase (IDH) belongs to a family of enzymes involved in glycometabolism. It is found in many living organisms and is one of the most mutated metabolic enzymes. In the current study, we identified novel IDH1-R132C inhibitors using docking-based virtual screening and cellular inhibition assays. A total of 100 molecules with high docking scores were obtained from docking-based virtual screening. The cellular inhibition assay demonstrated five compounds at a concentration of 10 μM could inhibit cancer cells harboring the IDH1-R132C mutation proliferation by > 50%. The compound (T001-0657) showed the most potent effect against cancer cells harboring the IDH1-R132C mutation with a half-maximal inhibitory concentration (IC50) value of 1.311 μM. It also showed a cytotoxic effect against cancer cells with wild-type IDH1 and normal cells with IC50 values of 49.041 μM and >50 μM, respectively. Molecular dynamics simulations were performed to investigate the stability of the kinase structure binding of allosteric inhibitor compound A and the identified compound T001-0657 binds to IDH1-R132C. Root-mean-square deviation, root-mean-square fluctuation, and binding free energy calculations showed that both compounds bind tightly to IDH1-R132C. In conclusion, the compound identified in this study had high selectivity for cancer cells harboring IDH1-R132C mutation and could be considered a promising hit compound for further development of IDH1-R132C inhibitors.
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作者：
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