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 Nterminal 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.

In silico Characterization of an Atypical MAPK Phosphatase of Plasmodium falciparum as a Suitable Target for Drug Discovery

“…ERRAT plots were generated to check structure quality of the template and homology structure using a nine‐residue sliding window . This process was repeated in an iterative fashion until all the residues in the plot were not below 95% as done previously . The quality of the final structure was also verified using Verify 3D, Procheck and Ramachandran plots .…”

Identification and screening of antimalarial phytochemical reservoir from northeastern Indian plants to develop PfRIO-2 kinase inhibitor

“…Recently, our laboratory has performed an in-depth structural and biochemical characterization of PFD0975w, a RIO-2 kinase (PfRIO-2) from P. falciparum kinome. There are number of biochemical and structural differences that exist between PfRIO-2 and other typical protein kinases or human RIO-2 (huRIO-2) to exploit it as an excellent drug target [16]. Our study highlights that PfRIO-2 has an N-terminal winged helix domain, kinase domain and a well-defined peptide binding region present within the catalytic core of the enzyme.…”

“…The 3-D structure of the PfRIO2 kinase (PFD0975w) was generated as described previously and used as target enzyme in docking experiment [16]. The docking experiment was performed by AutoDock 4.0 program suite of MGL Tools 1.5.4 software.…”

“…Docking protocol and parameters were kept constant for different phytochemicals molecules to avoid any procedural artifacts and compare binding affinity of different phytochemicals. For the substrate competition assay, PfRIO-2 complex with ATP model was generated as described previously [16] and used in docking as target enzyme instead of PfRIO-2 native structure. Docking protocol and other parameters were kept constant between docking experiments of phytochemicals with PfRIO-2 and PfRIO-2-ATP.…”

Molecular modelling, synthesis, and antimalarial potentials of curcumin analogues containing heterocyclic ring

“…RIO-1 (PFL1490w) and , RIO like kinases are present in malaria kinome with uncharacterized functions (www.plasmodb.org). The structural characterization of RIO-2 kinase of Plasmodium falciparum (PfRIO-2 kinase) explored having N-terminal DNA binding winged helix domain, a linker region and C-terminal kinase domain together with well defined ATP binding pocket with significantly different than that of the human RIO-2 kinase (Trivedi and Nag, 2012).…”