Exploration of N5-CAIR Mutase Novel Inhibitors from Pyrococcus horikoshii OT3: A Computational Study.

In bacterial and archaeal purine biosynthetic pathways, sixth step involves utilization of enzyme PurE, catalyzing the translation of aminoimidazole ribonucleotide to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) with carbon dioxide. The formation of CAIR takes place through an unstable intermediate N5-CAIR, played by two enzymes-N5-CAIR synthetase (PurK) and N5-CAIR mutase (PurE) that further catalyzes the reaction of N5-CAIR to CAIR. In this study, N5-CAIR mutase (PH0320) from Pyrococcus horikoshii OT3 (PurE) was considered. The three-dimensional structure of Pyrococcus horikoshii OT3 was modeled based on the structure of PurE from Escherichia coli. The modeled structure was subjected to molecular dynamics simulation up to 100 ns, and least energy structure from the simulation was subjected to virtual screening and induced fit docking to identify the best potent leads. A total of five best antagonists were identified based on their affinity and mode of binding leading with conserved residues Ser18, Ser20, Asp21, Ser45, Ala46, His47, Arg48, Ala72, Gly73, Ala75, and His77 promotes the activity of Ph-N5-CAIR mutase. In addition to molecular dynamics, absorption, digestion, metabolism, and excretion properties, binding free energy and density functional theory calculations of compounds were carried out. Based on analyses, compound from National Cancer Institute (NCI) database, NCI_826 was adjudged as the best potent lead molecule and could be suggested as the suitable inhibitor of N5-CAIR mutase.