An <i>in-silico</i> study of FIKK9.5 protein of <i>Plasmodium falciparum</i> for identification of therapeutics

The FIKK protein family, encompassing 21 serine-threonine protein kinases, is a distinctive cluster exclusive to the Apicomplexa phylum. Predominantly located in <i>Plasmodium falciparum</i> which is a malarial parasite, with a solitary gene identified in a distinct apicomplexan species, this family derives its nomenclature from - phenylalanine, isoleucine, lysine, lysine (FIKK), a conserved amino acid motif. Integral to the parasite's life cycle and consequential to malaria pathogenesis, the absence of orthologous proteins in eukaryotic organisms designates it as a promising antimalarial drug target. Among the FIKKs, FIKK9.5 plays a pivotal role in the parasite's development within red blood cells (RBCs). This investigation acquired the three-dimensional structure of FIKK9.5 and its ligands through extensive database searches and literature review. Computational screening of natural phytochemicals derived from plants traditionally used in antimalarial remedies was conducted by employing the Glide docking suite. AutoDock Vina was utilized to discern the inhibitor exhibiting optimal binding affinity. Subsequently, Molecular Dynamics (MD) simulations employing GROMACS validated Rufigallol as the most potent inhibitory compound against FIKK9.5. The robustness of the protein-ligand complex was scrutinized through a 200 nanosecond molecular dynamics (MD) trajectory. Trajectory analysis and determination of binding free energies were accomplished using MM-GBSA and MM-PBSA approaches. The ligand-binding exhibited sustained stability throughout the simulation, manifesting an approximate binding free energy of -25.5986 kcal/mol. This comprehensive computational study lays the groundwork for potential experimental validation in the laboratory, paving the way for the development of novel therapeutics targeting FIKK9.5 in the pursuit of innovative antimalarial.