Abstract

Calcium Dependent Protein Kinases are found in the Apicomplexan, algae, and plants; however, they are not reported in vertebrates and are regarded as excellent drug targets for pharmaceutical interventions. Calcium Dependent Protein Kinases of Cryptosporidium are probably involved in the regulation of invasion and egress process during the infection of the host cells. The previous study reported that after the Calcium Dependent Protein Kinase 1 gene, Calcium Dependent Protein Kinase 6 of Cryptosporidium parvum is expressed in all stages of the parasite (merozoites/schizonts as well as sexual stages) at a comparable level and makes it as a valid drug target. In this study, an attempt is made to address the similarity in sequences and phylogenetic study of Calcium Dependent Protein Kinase 6 (CDPK6) among Calcium Dependent Protein Kinases of Apicomplexans. Further, the three-dimensional structure determination of CDPK6 of C. parvum was performed through a molecular modeling approach followed by virtual screening of small-molecule inhibitors from different datasets. The best inhibitor from Tres Cantos Antimalarial Set with ID 11730 reported a binding affinity of −8.2 kcal/mol against CDPK6 of C. parvum. Furthermore, the reliability of the binding mode of the inhibitor is validated through a complex molecular dynamics simulation study for a time interval of 100 ns. The simulation study advocates that the inhibitor Tres Cantos Antimalarial Set_11730 formed a stable interaction with the predicted active site residues and can be considered for industrial pharmaceutical research in future.

Communicated by Ramaswamy H. Sarma

摘要

钙依赖性蛋白激酶存在于顶复门、藻类和植物中；然而，它们在脊椎动物中没有报道，被认为是药物干预的极好药物靶点。隐孢子虫的钙依赖性蛋白激酶可能参与宿主细胞感染过程中入侵和离开过程的调节。之前的研究报道了在钙依赖性蛋白激酶1基因之后，隐孢子虫的钙依赖性蛋白激酶6在寄生虫的所有阶段（裂殖子/裂殖体以及有性阶段）都以相当的水平表达，使其成为有效的药物靶点。在本研究中，试图解决顶复门类钙依赖性蛋白激酶之间钙依赖性蛋白激酶 6 (CDPK6) 的序列相似性和系统发育研究。此外，通过分子建模方法对C. parvum的 CDPK6 进行三维结构测定，然后从不同数据集中虚拟筛选小分子抑制剂。来自 Tres Cantos Antimalarial Set 的最佳抑制剂 ID 为 11730，据报道 对C. parvum 的CDPK6 的结合亲和力为 -8.2 kcal/mol. 此外，通过复杂的分子动力学模拟研究验证了抑制剂结合模式的可靠性，时间间隔为 100  ns。模拟研究主张抑制剂Tres Cantos Antimalarial Set_11730与预测的活性位点残基形成稳定的相互作用，未来可考虑用于工业药物研究。

由 Ramaswamy H. Sarma 交流