Repurposing FDA-Approved Agents to Develop a Prototype Helicobacter Pylori Shikimate Kinase (HPSK) inhibitor: A Computational Approach Using Virtual Screening, MM-GBSA Calculation, MD Simulations, and DFT Analysis

Background/ Objectives: Helicobacter pylori infects approximately half of the global popu-lation, causing chronic gastritis, peptic ulcers, and gastric cancer, a leading cause of can-cer mortality. While current therapies face challenges from rising antibiotic resistance, particularly to clarithromycin, alongside treatment complexity and costs, the World Health Organization has prioritized the development of new antibiotics to combat this high-risk pathogen. In this study, we employed computer-aided drug design (CADD) methodologies, including molecular docking, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) analysis, molecular dynamics (MD) simulations, and Density Functional Theory (DFT) calculations, to explore the potential repurposing of FDA-approved agents as inhibitors of Helicobacter pylori shikimate kinase (HpSK). Meth-ods: Using the Glide module, the HTVS method was initially applied to screen 1,615 FDA-followed by extra-precision (XP) docking for the obtained 111 hits. The obtained XP scores were used to confine the results to those hits with a score above the reference ligand, Shikimate, score. This yielded 31 final hits with an XP score above -5.867. MM-GBSA cal-culations were performed on these top candidates and the reference ligand to refine the analysis and compounds’ prioritization. Results: The 31 compounds displayed binding free energy (ΔGbind) values ranging from 3.61 to -55.92 kcal/mol, with shikimate exhibiting a ΔGbind of -34.24 kcal/mol and ten hits having lower ΔGbind value. Out of these ten, three drugs—Dolutegravir, Cangrelor, and Isavuconazonium—were selected for further analy-sis based on their drug-like properties. Robust and stable binding profiles for both Isavuconazonium and Cangrelor were verified via molecular dynamics simulation. Addi-tionally, Density Functional Theory (DFT) analysis was conducted, and the Highest Oc-cupied Molecular Orbitals (HOMO), Lowest Unoccupied Molecular Orbitals (LUMO), and the energy gap (HLG) between them were calculated. All three drug candidates displayed lower (HLG) values than shikimate, suggesting higher reactivity and more efficient elec-tronic transitions than the reference ligand. Conclusions: These findings suggest that the identified drugs, although not optimal for direct repurposing, would serve as promising leads against Helicobacter pylori shikimate kinase. These drugs could be valuable leads for experimental assessment and further optimization, particularly with no prototype yet has been identified. In terms of potential of clinical repurposing, the results pointed to diflunisal as a promising candidate for further testing.