Characterization of the Plasmodial GTP Cyclohydrolase I enzyme as a potential antimalarial drug target using computational approaches

Malaria remains a global health problem. About a quarter of a billion people are infected annually, including young children, pregnant women, and non-immune travelers. Majority of the cases occur in Sub-Saharan Africa, making it a malaria-endemic region. The efficacy of current anti-malarial drugs has reduced significantly due to the parasites’ developed resistance, causing a delay in clearing it from the infected host blood system. With the problem of drug resistance on the rise, the need to develop new anti-malarial treatment strategies has become crucial. In this study, we characterize the malaria parasite GTP cyclohydrolase (GCH1) enzyme as an alternative antimalarial drug target. Sequence, motif, and phylogenetic analyses were performed to identify unique sequence features. Accurate 3D models of the five human-infective malaria parasites were calculated. Drug candidates from the South African Natural Compounds Database (SANCDB, sancdb.rubi.ru.ac.za) were screened against the GCH1 enzyme. All-atom molecular dynamics (MD) simulations were carried out using the GROningen MAchine for Chemical Simulations (GROMACS) and Chemistry at HARvard Molecular Mechanics (CHARMM) MD packages to analyze the enzyme dynamical properties.