In Silico Characterization of Atypical Kinase PFD0975w from Plasmodium Kinome: A Suitable Target For Drug Discovery

Abstract

RIO-2 kinase is known to regulate ribosome biogenesis and other cell cycle events. The 3D model of ATP bound and an unbound form of PFD0975w was generated using AfRIO-2 crystal structure 1TQI, 1ZAO as template employing Modeller9v7 program. Structural characterization identified N-terminal winged helix domain (1-84), C-terminal kinase domain (148-275), and presence of other critical residues known for ATP binding and kinase activity. Using Q-site and pocket finder, a number of well-defined substrate (peptide) binding regions were identified in the catalytic core of the protein. The peptide binding regions were further validated by molecular modeling a non-specific polyalanine peptide and a sequence-specific peptide2 into these sites to generate a stable PFD0975w/peptide complexes. Peptide fits well into identified pocket on PFD0975w and makes extensive interaction with the protein residues. These newly identified peptide binding sites potentially give opportunity to design a specific inhibitor against PFD0975w. There are subtle but significant differences between Plasmodium falciparum and human RIO-2 to exploit PFD0975w for drug development. In conclusion, our finding will let us to design effective chemotherapy against malaria parasite exploiting PFD0975w as a drug target.