School of Biotechnology, KIIT University, Bhubaneswar-751024, Odisha, India.
School of Biotechnology, KIIT University, Bhubaneswar-751024, Odisha, India.
J Theor Biol. 2019 Jan 14;461:254-267. doi: 10.1016/j.jtbi.2018.10.045. Epub 2018 Oct 27.
Calcium-Dependent Protein Kinase 5 (CDPK5) protein is one of the family members of a calcium-dependent protein kinase that is found in plants and some species of protozoa which includes Plasmodium falciparum (Pf), the pathogen responsible for malaria. CDPKs regulate many biological processes in Apicomplexans such as Plasmodium, Toxoplasma or Cryptosporidium. The study addresses the similarity in sequences and evolutionary relationship of CDPK5 across Apicomplexans. Further, the three-dimensional structural conformation of PfCDPK5 is generated through homology modeling. Molecular dynamics simulation of the homology model for a time interval of 40 ns resulted in a stable conformation of the PfCDPK5 protein. Inhibitor identification was carried out from computational screening of known anti-malarial compounds. The reliability of the binding mode for the best inhibitor compound MMV687246 was validated through a complex molecular dynamics study. This findings advocates that MMV687246 from Pathogen Box as the best inhibitor against PfCDPK5 protein and can be considered for experimental validation study in future.
钙依赖蛋白激酶 5（CDPK5）蛋白是钙依赖蛋白激酶家族的成员之一，存在于植物和某些原生动物物种中，包括疟原虫（Pf），疟原虫是疟疾的病原体。CDPKs 调节疟原虫、弓形虫或隐孢子虫等顶复门生物的许多生物学过程。本研究探讨了 CDPK5 在顶复门生物中的序列相似性和进化关系。此外，还通过同源建模生成了 PfCDPK5 的三维结构构象。同源模型的分子动力学模拟在 40ns 的时间间隔内产生了 PfCDPK5 蛋白的稳定构象。通过对已知抗疟化合物的计算筛选进行抑制剂鉴定。通过对最佳抑制剂化合物 MMV687246 的复合物分子动力学研究验证了结合模式的可靠性。这些发现表明，Pathogen Box 中的 MMV687246 是 PfCDPK5 蛋白的最佳抑制剂，可考虑在未来进行实验验证研究。
