In silico evaluation and prioritization of secondary metabolites of Amphipterygium adstringens as potential inhibitors of the LpxC enzyme of multidrug-resistant Acinetobacter baumannii using computer-aided rational drug design strategies.

Introduction: Acinetobacter baumannii is recognized as a critical priority pathogen and its impact on public health. In this context, LpxC, a zinc-dependent metalloenzyme essential for lipid A biosynthesis, has significant clinical and pharmaceutical importance as it has no human homolog. At the same time, the therapeutic potential of secondary metabolites from Amphipterygium adstringens against multidrug-resistant ESKAPE pathogens has not been systematically explored.

Objective: To evaluate the potential of Amphipterygium adstrigens secondary metabolites as possible inhibitors of the enzyme LpxC from Acinetobacter baumannii, using in silico strategies, in order to identify and prioritize compound candidates for future in vitro and in vivo investigations.

Materials and Methods: The structure of LpxC was modeled using AlphaFold, and zinc atom was added by homology at the coordinates x =5.503, y =1.117, and z = -4.696, followed by energy minimisation. Ligand selection was performed based on scientific literature using the PF-5081090 as the reference compound. Molecular docking studies were then carried out using the genetic algorithm in AutoDock 4.

Results: The triterpenoids: eburic, 10-oxo-oleanolic acids and a hydroxyoleanane derivative, showed favourable binding affinities toward the LpxC enzyme, with predicted binding free energies of −8.89, −8.83, and −8.33 kcal/mol, respectively. These compounds occupied the catalytic pocket and interacted with the same histidines 237 and 264, containing binding region as the reference inhibitor.

Conclusions: The results identify three triterpenoids as promising scaffolds for developing novel LpxC inhibitors against Acinetobacter baumannii. Their favourable binding affinities support further molecular dynamics studies and experimental validation to confirm their therapeutic potential.