Rusina Polina, Gandalipov Erik, Abdusheva Yana, Panova Maria, Burdenkova Alexandra, Chaliy Vasiliy, Brachs Maria, Stroganov Oleg, Guzeeva Ksenia, Svitanko Igor, Shtil Alexander, Novikov Fedor
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Avenue, 119991 Moscow, Russia.
Laboratory of Solution Chemistry and Advanced Materials Technologies, ITMO University, 9 Lomonosov Street, 191002 Saint Petersburg, Russia.
Cancers (Basel). 2023 Jul 25;15(15):3766. doi: 10.3390/cancers15153766.
The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds - containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of - with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.
细胞周期蛋白依赖性蛋白激酶（CDK）抑制剂的合理设计需要开发精确预测小分子抗癌候选药物选择性和活性的方法。为了降低低选择性化合物的一般毒性，我们在此探索了泛CDK抑制剂PHA-793887的咪唑-4-N-乙酰胺取代衍生物的新化学类型。使用基于非平衡（NEQ）热力学的方案，分析了在支架外围含有脂肪族甲基或芳香族基团的新合成化合物与CDK1、-2、-5和-9结合的相对自由能预测。该方法能够证明计算出的与各个靶点相互作用参数与体外激酶试验中抑制效力值之间具有良好的相关性。我们提供证据支持NEQ热力学作为一种节省时间、精确且高效的方法来生成临床相关抗癌靶点的化学抑制剂。
