Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum

• DOI: 10.1042/bcj20200045
• Publication Date: 2020-05-14T01:24:14Z
• Authors: Ravi Jain; Sakshi Gupta; Manoj Munde; Soumya Pati; Shailja Singh
• Keywords: 0301 basic medicine; Antimalarials; 03 medical and health sciences; Erythrocytes; Drug Design; Plasmodium falciparum; Protozoan Proteins; Animals; Humans; Malaria, Falciparum; Protein Kinases; 3. Good health

Upon Plasmodium falciparum merozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub intra-erythrocytic proliferative stages parasite. Given its high abundance and multidimensional attributes parasite life-cycle, this lucrative target for designing antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection 10,000 drug-like molecules, resulted 18 compounds complementing ATP-binding pocket CDPK1. In vitro screening toxicity mammalian cells revealed that these are non-toxic nature. Furthermore, SPR analysis demonstrated differential binding affinity towards recombinantly purified CDPK1 protein. Selection lead compound was performed by evaluating their inhibitory effects on phosphorylation ATP activities biophysical evaluations ITC FS driven formation energetically favorable non-covalent interactions, with different constants presence absence Ca2+, TSA authenticated stability bound complex. Finally, strongly inhibited growth P. vitro. Conceivably, propose novel CDPK1-selective inhibitor, step developing pan-CDPK kinase inhibitors, prerequisite cross-stage anti-malarial protection.