Abstract：
The pyrimidine and fused pyrimidine ring systems play vital roles to inhibit the c-Src kinase. The Src kinase is made of different domains but the kinase domain is responsible for inhibition of Src kinase. In which the kinase domain is the main domain that is made of several amino acids. The Src kinase is inhibited by its inhibitors when it is activated by phosphorylation. Although dysregulation of Src kinase caused cancer in the late nineteenth century, medicinal chemists have not explored it extensively; therefore it is still regarded as a cult pathway. There are numerous FDA-approved drugs on the market, yet novel anticancer drugs are still in demand. Existing medications have adverse effects and drug resistance owing to rapid protein mutation. In this review, we discussed the activation process of Src kinase, chemistry of pyrimidine ring and its different synthetic routes, as well as the recent development in c-Src kinase inhibitors containing pyrimidine and their biological activity, SAR, and selectivity. The c-Src binding pocket has been predicted in detail to discover the vital amino acids which will interact with inhibitors. The potent derivatives were docked to discover the binding pattern. The derivative 2 established three hydrogen bonds with the amino acid residues Thr341 and Gln278 and had the greatest binding energy of -13.0 kcal/mol. The top docked molecules were further studied for ADMET studies. The derivative 1, 2, and 43 did not show any violation of Lipinski\'s rule. All derivatives used for the prediction of toxicity showed toxicity.
摘要：
嘧啶和稠合嘧啶环系统在抑制c-Src激酶中起着至关重要的作用。Src激酶由不同的结构域组成,但激酶结构域负责抑制Src激酶。其中激酶结构域是由几个氨基酸组成的主要结构域。当Src激酶被磷酸化激活时,其抑制剂抑制。尽管Src激酶的失调在19世纪后期引起了癌症，药物化学家还没有对它进行广泛的探索；因此它仍然被视为邪教途径。市场上有许多FDA批准的药物，然而，新型抗癌药物仍在需求中。现有的药物由于快速的蛋白质突变而具有副作用和耐药性。在这次审查中,我们讨论了Src激酶的激活过程，嘧啶环的化学及其不同的合成路线,以及含嘧啶的c-Src激酶抑制剂及其生物活性的最新进展，SAR,和选择性。已详细预测了c-Src结合袋，以发现将与抑制剂相互作用的重要氨基酸。将有效的衍生物对接以发现结合模式。衍生物2与氨基酸残基Thr341和Gln278建立了三个氢键,并且具有-13.0kcal/mol的最大结合能。进一步研究了顶部对接的分子用于ADMET研究。衍生工具1、2和43没有显示出任何违反Lipinski规则的行为。用于预测毒性的所有衍生物均显示毒性。
