Research program title
Modeling Comparative Enzyme Inhibition
There is mounting experimental evidence that nitric oxide (NO) donors are promising antiparasitics with GAPDH, a central glycolytic enzyme, as a key target in parasites that rely on glycolysis for their energy supply. Effective antiparasitics must selectively inhibit the parasite enzyme but not the host analog. To complement experimental data and to advance our research on this important issue, state-of-the-art computational and theoretical chemistry approaches will be used to fully develop our understanding of the comparative inhibition of parasite vs human GAPDH. Specifically, we will probe nitroglycerin docking to P. falciparum, T. brucei, T. cruzi and human GAPDHs and perform molecular dynamics (MD) simulations of the docked structures to elucidate differences in drug binding. Additionally, other NO donors, including GSNO and CysNO, will be docked onto the GAPDHs to predict their comparative reactivity as potential drugs. The numerous GAPDH crystal structures in the Protein Data Bank (PDB) will provide an excellent platform for comparative computational modeling at the molecular level. The results are expected to establish a new mechanistic model for GAPDH inhibition and demonstrate the power of a comparative computational approach in probing biochemical function and drug design.
Academic qualifications required
- PhD in chemistry, biochemistry or biophysics with experience in computer simulations and quantum chemistry.
- Expertise with molecular dynamics software packages desirable.