Ho Leung Ng
Associate Professor, Biochemistry and Molecular Biophysics
Kansas State University
Identifying antimalarial kinase drug targets (2018-19)
New antimalarial drugs with novel mechanisms are desperately needed. We are members of the Open Source Malaria (OSM) consortium with a research model inspired by the culture of open source software. We seek to experimentally identify the target of one of OSM’s most
promising drug leads. We will also screen target candidates for vulnerability against kinase inhibitor drugs.
OSM has identified OSM-S-106 as a potent antimalarial. OSM-S-106 shows no cytotoxicity against normal hepatocytes and has favorable pharmacokinetic stability. No mechanism of action is known. By analyzing computational ligand-based similarity and inverse target docking, we have identified Plasmodium falciparum kinases as the likeliest targets of OSM-S-106. We will test our hypothesis by screening OSM S-106 and analogs against the seven most promising kinase targets. We are partnering with the University of Kansas (KU) Protein Production Core Lab to produce these seven kinases. Our lab will perform kinase inhibitor assays for the seven kinases against OSM-S-106. The KU Bio-NMR Core Lab will measure the binding affinity of OSM-S-106 against these seven kinases using saturation transfer difference experiments. Results will drive the long-term structure-based drug design of OSM-S-106 analogs.
To further exploit the value of our recombinant kinases, we will screen them against known human kinase inhibitors for potential repurposing. Identifying clinically used and advanced stage drugs will provide leads best poised for rapid translation to malaria patients.
Specific Aim 1. Express the top seven candidate kinase targets of OSM-S-106. Perform ligand binding and enzyme inhibition assays to identify potential targets of OSM-S-106.
Specific Aim 2. Screen clinical and advanced stage kinase inhibitor drugs against expressed kinases as candidates for potential repurposing as antimalarial agents.