Malaria is a deadly parasitic infection that afflicts millions of people annually. The most virulent is Plasmodium falciparum, especially in the tropics. Many drugs are used to target malaria, but resistance is a major bottleneck, even in artemisinin compounds. The cyclic GMP (cGMP)-dependent protein kinase (PKG) of P. falciparum plays key roles in various stages of the Plasmodium life cycle. The presence of threonine in the PKG's active site, rather than bulkier methionine in humans, offers high selectivity in drug design. The alkaloidal natural compounds (NC) offer a wide structural complexity from which to execute a robust drug discovery campaign. In this study, we intend to use alkaloidal NC from plants with reported antimalaria activities to design potent compounds active against plasmodial PKG. We will employ various rounds of molecular docking, molecular dynamics simulations, pharmacophore modeling and hit optimization involving BiosolvelT® tools to execute this project.
Shadrach intends to achieve the following milestones:
- To have identified binding pockets of Plasmodium falciparum PKG using DoGSiteScorer® and conducted Molecular Docking with alkaloidal NC
- To have carried out Molecular Dynamics Simulations of first six hit compounds and built a pharmacophore model using SeeSar®.
- To have conducted Virtual Library Screening (VLS) of BiosolveIT® chemical databases using the pharmacophore model