Exploring the Possible Allosteric Binding Sites of <i>Plasmodium falciparum</i> Hypoxanthine‐Guanine‐Xanthine Phosphoribosyl Transferase (<i>Pf</i>HGXPRT) with Iso‐Mukaadial Acetate and Ursolic Acid Acetate Using Computational Approaches

Abstract Malaria parasites use PfHGXPRT to convert 6‐oxopurine substrate bases to their respective nucleotides, essential for parasite replication within the human host. Inhibitors targeting Pf HGXPRT may also bind to the human homolog, Hs HGPRT 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 Pf HGXPRT that are distinct from Hs HGPRT. 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 Pf HGXPRT. They exhibited docking scores of −4.3 and −3.3 kcal/mol respectively. The biomolecular behaviour of Pf HGXPRT and Hs HGPRT bound to IMA at pocket II was investigated with molecular dynamics and IMA‐ Pf HGXPRT had more stable ligand complex. IMA binding at Pf HGXPRT pocket II involved different residues compared to Hs HGPRT as evident with protein alignment, thus suggesting it as a potential allosteric site that can be explored further to understand the activity of Pf HGXPRT.