Malaria is a global challenge, and its infection is propagated through Plasmodium falciparum, an obligate human parasite. The genome of P. falciparum encodes many proteases that play significant roles in their survival and pathogenesis thus being considered as attractive drug targets. P. falciparum metacaspase-3 (PfMCA3) is one such protease and a validated drug target to control malarial infection. First, we modeled the three-dimensional structure of PfMCA3 and predicted its ligand-binding pocket. The structural features of PfMCA3 were used for virtual screening followed by docking and molecular dynamics (MD) simulation studies to identify potent inhibitors. We used an in-house library of 513 compounds for screening to identify lead molecule fits well in the active site pocket of PfMCA3. The binding affinity and mechanism were investigated by combined docking and MD simulation studies. Docking studies reveal that the selected compounds are forming enough number of non-covalent interactions to the PfMCA3. In the enzyme inhibition assay, one of the selected compounds, H6 was found with appreciable inhibitory potential. MD simulation studies further support the binding of compound H6 with PfMCA3 and formation of a stable complex throughout the simulation trajectory. Taken together, we proposed that compound H6 is a promising lead scaffold that can be further exploited as a potential inhibitor of PfMCA3 for therapeutic management of malarial infection.Communicated by Ramaswamy H. Sarma.
Keywords: Malaria; PfMCA3; Plasmodium falciparum; drug design; metacaspase-3; molecular dynamics simulation; molecular modeling; proteases.