Repurposing the angiotensin II receptor blocker valsartan to inhibit penicillin-binding protein 3 and its mutants in Haemophilus influenzae: a comprehensive in silico approach
Abstract
Introduction Ampicillin-resistant Haemophilus influenzae ( H. influenzae ) has been recently designated as a medium-priority bacterial pathogen in 2024 by the World Health Organization (WHO). This pathogen is responsible for a wide range of infections, including sinusitis, acute otitis media, and pneumonia, as well as severe and life-threatening conditions such as bacteremia, meningitis, and epiglottitis. In this context, drug repurposing has emerged as an effective strategy, as the pharmacokinetic properties and safety profiles of approved drugs are already well established, allowing for faster development compared to conventional drug discovery approaches. Methods In the current study, U.S. Food and Drug Administration (FDA)-approved drugs with structural similarity to ampicillin were filtered and evaluated using in silico approaches. Their pharmacokinetic properties and antimicrobial potential were assessed. Molecular docking and simulation studies were conducted to evaluate binding affinities toward wild-type penicillin-binding protein 3 (PBP 3WT ) and its common mutants (PBP3 N526K and PBP3 R517H ). Results An angiotensin II receptor blocker, valsartan, demonstrated strong binding affinity toward all three target proteins, with values of −11.8 kcal/mol for PBP3 WT , −11.4 kcal/mol for PBP3 N526K , and −11.1 kcal/mol for PBP3 R517H . The drug also exhibited strong intermolecular interactions and maintained stable binding with all three PBP3 variants during molecular…
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