Repurposing FDA-Approved Agents to Develop a Prototype Helicobacter pylori Shikimate Kinase (HPSK) Inhibitor: A...

Area of Science:

• Computational chemistry and drug discovery
• Microbiology and infectious diseases
• Pharmacology and medicinal chemistry

Background:

• Helicobacter pylori infection affects half the global population, causing severe gastrointestinal diseases.
• Rising antibiotic resistance and treatment challenges necessitate novel therapeutic strategies.
• The World Health Organization highlights the urgent need for new antibiotics against H. pylori.

Purpose of the Study:

• To identify potential drug repurposing candidates against Helicobacter pylori shikimate kinase (HpSK).
• To explore FDA-approved agents as novel inhibitors for H. pylori.
• To leverage computer-aided drug design (CADD) for novel therapeutic leads.

Main Methods:

• Screening of 1615 FDA-approved agents using molecular docking (HTVS and XP).
• Prioritization of hits using MM-GBSA analysis and molecular dynamics (MD) simulations.
• Evaluation of electronic properties via Density Functional Theory (DFT) calculations.

Main Results:

• 31 compounds showed significant binding affinity to HpSK, with 10 exhibiting superior binding free energy compared to shikimate.
• Dolutegravir, Cangrelor, and Isavuconazonium demonstrated stable binding profiles and favorable electronic properties.
• Diflunisal emerged as a particularly promising candidate for further clinical repurposing investigation.

Conclusions:

• Identified drug candidates serve as valuable starting points for developing new H. pylori treatments.
• Further experimental validation and optimization of these leads are recommended.
• Diflunisal shows potential for clinical repurposing against H. pylori infections.