Computationally Generated Plant-Derived Berberine-Based Hybrid Compounds as Potential Dual Binders to Staphylococcus...

Staphylococcus aureus (S. aureus) remains a major global pathogen and a significant public health concern due to its antibiotic resistance. This has spurred the search for new treatments, resulting in the discovery of two promising targets: FtsZ and FabI. Naturally occurring compounds berberine and lipophilic acids are known to bind these enzymes, respectively. This study aims to improve berberine's binding affinity for FtsZ and enhance its interaction with FabI by designing hybrid compounds that could serve as dual inhibitors, targeting both active and allosteric sites. Forty-eight hybrids, derived from berberine and lipophilic acids with 10 to 22 carbons, were modeled. Molecular docking against five S. aureus enzyme crystal structures identified six compounds with geranic acid chains (1s, 1t, 1u, 2s, 2t, 2u) that showed the strongest binding. Among these, 2s, 2t, and 1t showed the greatest affinity for FtsZ, while 2u, 1u, and 1s targeted FabI, with binding energies around -8.2 to -10.5 kcal/mol. QSAR models estimated MICs within known inhibitor ranges, implying potential effectiveness. Hydrophobic and flexible features correlated with stronger interactions and activity. ADMET analysis indicated low toxicity for these hybrids. Modifying berberine with lipophilic acids appears to be a promising approach for developing plant-based dual inhibitors against S. aureus.