Heliocide H2 and cadinatriene glucopyranoside as promising dual β-lactamase inhibitors against antibiotic resistance: an integrated computational study

Antibiotic resistance mediated by β-lactamase enzymes poses a major obstacle to the effective treatment of bacterial infections. Among these enzymes, serine β-lactamases and metallo β-lactamases are of particular concern, as they hydrolyze β-lactam antibiotics, rendering them ineffective. This study aimed to identify putative dual β-lactamase inhibitor candidates with predicted activity against both classes of β-lactamases using a comprehensive in silico approach. A curated library of 163 phytochemicals from Gossypium hirsutum L. was compiled from literature and chemical databases. Of these, 32 compounds exhibited higher docking scores than the standard inhibitors (boronic acid and meropenem) against both targets. The top 10 dual inhibitors, selected based on Lipinski’s rule of five and additional drug-likeness criteria, were subjected to further pharmacological evaluation. Heliocide H2 and Cadinatriene Glucopyranoside emerged as lead candidates based on their favorable predicted binding interactions, pharmacophoric features, and medicinal chemistry profiles. Interaction analysis revealed that both compounds formed key active-site interactions in both enzyme classes, including hydrogen bonding with SER-64 and zinc coordination in metallo β-lactamases. Pharmacokinetic profiling predicted high gastrointestinal absorption and no blood-brain barrier penetration, while PASS predictions suggested possible broad-spectrum antibacterial potential. The 200ns Molecular dynamics simulations suggested comparatively greater stability of Heliocide H2, as evidenced by lower radius of gyration (Rg), stable solvent accessible surface area (SASA) profiles, and a greater number of hydrogen bonds. Principal component analysis (PCA) and free energy landscape (FEL) analyses further demonstrated that Heliocide H2 maintained a stable conformational state throughout the simulation. Moreover, MM/PBSA binding free energy calculations showed that the Heliocide H2–metallo β-lactamase complex exhibited the most favorable binding energy (ΔG = − 21.2 kcal/mol). These findings support the prioritization of heliocide H2 and cadinatriene glucopyranoside as putative dual β-lactamase inhibitor candidates with predicted interactions with both serine and metallo β-lactamases. However, further in vitro and in vivo studies are required to validate their inhibitory activity, safety, pharmacological properties, and therapeutic potential.