Cyclin-dependent kinase 8 (CDK8) has emerged as a promising target for inhibiting cancer cell function, intensifying efforts towards the development of CDK8 inhibitors as potential cancer therapeutics. Mutations in CDK8, a protein kinase, are also implicated as a primary factor associated with tumor formation. In this study, we identified potential inhibitors through virtual screening for CDK8 and single amino acid mutations in CDK8, namely D173A (Aspartate 173 mutate to Alanine), D189N (Aspartate 189 mutate to Asparagine), T196A (Threonine 196 mutate to Alanine) and T196D (Threonine 196 mutate to Aspartate). Four databases (CHEMBEL, ZINC, MCULE, and MolPort) containing 65,209,131 molecules have been searched to identify new inhibitors for CDK8 and its single mutations. In the first step, structure-based pharmacophore modeling in the Pharmit server was used to select the compounds to know the inhibitors. Then molecules with better predicted drug-like molecule properties were selected. The final filter used to select more effective inhibitors among the previously selected molecules was molecular docking. Finally, 13 hits for CDK8, 11 hits for D173A, 11 hits for D189N, 15 hits for T196A, and 12 hits for T196D were considered potential inhibitors. A majority of the virtual screening hits exhibited satisfactorily predict pharmacokinetic characteristics and toxicity properties.

中文翻译：

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通过计算机辅助药物发现成功发现潜在的 CDK8 抑制剂并分析癌症治疗的氨基酸突变

细胞周期蛋白依赖性激酶 8 (CDK8) 已成为抑制癌细胞功能的有前景的靶标，加大了开发 CDK8 抑制剂作为潜在癌症治疗药物的力度。 CDK8（一种蛋白激酶）的突变也被认为是与肿瘤形成相关的主要因素。在本研究中，我们通过虚拟筛选 CDK8 和 CDK8 中的单个氨基酸突变，确定了潜在的抑制剂，即 D173A（天冬氨酸 173 突变为丙氨酸）、D189N（天冬氨酸 189 突变为天冬酰胺）、T196A（苏氨酸 196 突变为丙氨酸）和 T196D （苏氨酸 196 突变为天冬氨酸）。已搜索包含 65,209,131 个分子的四个数据库（CHEMBEL、ZINC、MCULE 和 MolPort），以鉴定 CDK8 及其单突变的新抑制剂。第一步，使用 Pharmit 服务器中基于结构的药效团建模来选择化合物以了解抑制剂。然后选择具有更好预测的类药物分子特性的分子。用于在先前选择的分子中选择更有效的抑制剂的最终过滤器是分子对接。最后，CDK8的13个命中、D173A的11个命中、D189N的11个命中、T196A的15个命中和T196D的12个命中被认为是潜在抑制剂。大多数虚拟筛选结果都令人满意地预测了药代动力学特征和毒性特性。