Targeting XGHPRT enzyme to manage Helicobacter pylori induced gastric cancer: A multi-pronged machine learning, artificial intelligence and biophysics-based study

Abstract

Helicobacter pylori infects the stomach mucosa of over half of the global population and can lead to gastric cancer. This pathogen has demonstrated resistance to many frequently prescribed antibiotics, thereby underscoring the pressing need to identify novel therapeutic targets. The inhibition or disruption of nucleic acid biosynthesis constitutes a promising avenue for either restraining or eradicating bacterial proliferation. The synthesis of RNA and DNA precursors (6-oxopurine nucleoside monophosphates) is catalyzed by the XGHPRT enzyme. In this study, using machine learning, artificial intelligence and biophysics-based software, CHEMBRIDGE-10000196, CHEMBRIDGE-10000295, and CHEMBRIDGE-10000955 were predicted as promising binders to the XGHPRT with a binding score of −14.20, −13.64, and −12.08 kcal/mol, respectively, compared to a control guanosine-5′-monophosphate exhibiting a docking score of −10.52 kcal/mol. These agents formed strong interactions with Met33, Arg34, Ala57, Asp92, Ser93, and Gly94 at short distance. The docked complexes of the lead compounds exhibited stable dynamics during the simulation time with no global changes noticed. The docked complexes demonstrate a significantly stable MM-GBSA and MM-PBSA net binding energy of −60.1 and −61.18 kcal/mol for the CHEMBRIDGE-10000196 complex. The MM-GBSA net energy value of the CHEMBRIDGE-10000295 complex and the CHEMBRIDGE-10000955 complex is −71.17 and −65.29 kcal/mol, respectively. The CHEMBRIDGE-10000295 and CHEMBRIDGE-10000955 complexes displayed a net value of −71.91 and −63.49 kcal/mol, respectively, as per the MM-PBSA. The major driving intermolecular interactions for the docked complexes were found to be the electrostatic and van der Waals. The three filtered molecules hold potential for experimental evaluation of their potency against the XGHPRT enzyme.