Structural and functional characterization of the egress and invasion machinery of the Malaria parasite: proposing a new way forward in malaria therapeutics from an atomistic perspective.

Abstract

The past decade has witnessed numerous efforts to control the invasive tactics of the malarial parasite, including focused research towards selective malarial inhibitors of Plasmodium falciparum, the most lethal strain of the Plasmodium species. The recent discovery of the key mediators of egress and erythrocyte invasion of the malaria parasite has opened a new avenue that may be harnessed for the development of effective therapeutics that may permanently eradicate the malaria virus. These new parasitic targets of P. falciparum are PIX and PX and have gained considerable attention in drug discovery pipelines however, the absence of crystal structures of these enzymes evidenced a lack in structural information, as there is currently little known regarding the structural dynamics, active site domains and the mechanism of inhibition of these enzymes. This has therefore led to the modeling of the 3D protein structure of each enzyme to gain a fundamental understanding regarding the structural and functional characteristics that may be visualized from an atomistic perspective. The emergence of new drug targets has led to the integral use of computational techniques including molecular modeling, molecular docking, virtual screening protocols and molecular dynamic simulations which allow chemists to evaluate and assess millions of compounds and thus funnel out potential lead drugs. These in silico techniques further justify the current use of Computer-Aided Drug Design as a cost-effective approach to fast track the drug discovery process. The above-mentioned techniques, amongst a vast range of other computational tools were integrated in this study to provide insight into conformational changes that elucidate potential inhibitory mechanisms, identification of the active site cleft, characterization and pharmacophoric features leading to novel small molecule inhibitors. This study focused on analysing the flap dynamics specific to the aspartic protease family of enzymes using a defined set of parameters to map out the binding domain for the design of potential antimalarial drugs. To gain a molecular perspective of the conformational binding of two proposed experimental drugs which showed substantial inhibitory activity against PIX and PX molecular dynamic simulations were performed and further evaluated employing in silico thermodynamic analysis to provide insight into the proposed binding of mode of each inhibitor, highlighting the key moieties required for binding. A pharmacophoric model was also generated using in silico tools to screen for tailored inhibitors specific to PIX. The aim of this study was to generate fundamental insight into the structural and functional characterization of two prominent targets that play an indispensable role in survival of the malaria virus. The implementation of thebinformation extracted from this study, may provide a structural outline for molecular biologists, and pharmaceutical scientists to aid in the design of novel antimalarial therapeutics.