Exploring the Possible Allosteric Binding Sites of Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyl Transferase (PfHGXPRT) with Iso-Mukaadial Acetate and Ursolic Acid Acetate Using Computational Approaches

Malaria parasites use PfHGXPRT to convert 6-oxopurine substrate bases to their respective nucleotides, essential for parasite replication within the human host. Inhibitors targeting PfHGXPRT may also bind to the human homolog, HsHGPRT due to the conserved active site residues. This may lead to unintended toxicity and side effects. To address this, we employed an in silico binding pocket workflow involving FTMap, FTSite, Protein Allosteric and Regulatory Sites (PARS), and Protein Allosteric Sites Server (PaSSer) to identify potential allosteric sites on PfHGXPRT that are distinct from HsHGPRT. In addition to the active site (pocket I), pockets II and IV were identified as potential allosteric sites. Pocket II was located close to pocket I. Potential inhibitors, Iso-mukaadial acetate (IMA) and Ursolic acid acetate (UAA) were docked into pocket II of PfHGXPRT. They exhibited docking scores of −4.3 and −3.3 kcal/mol respectively. The biomolecular behaviour of PfHGXPRT and HsHGPRT bound to IMA at pocket II was investigated with molecular dynamics and IMA- PfHGXPRT had more stable ligand complex. IMA binding at PfHGXPRT pocket II involved different residues compared to HsHGPRT as evident with protein alignment, thus suggesting it as a potential allosteric site that can be explored further to understand the activity of PfHGXPRT.