A computational odyssey: uncovering classical β-lactamase inhibitors in dry fruits

In the antibacterial arsenal, β-lactams have held a prominent position, but increasing resistance due to unauthorized use and genetic factors requires new strategies. Combining β-lactamase inhibitors with broad-spectrum β-lactams proves effective in combating this resistance. ESBL producers demand new inhibitors, leading to the exploration of plant-derived secondary metabolites for potent β-lactam antibiotics or alternative inhibitors. Using virtual screening, molecular docking, ADMET analysis, and molecular dynamic simulation, this study actively analyzed the inhibitory activity of figs, cashews, walnuts, and peanuts against SHV-1, NDM-1, KPC-2, and OXA-48 β-lactamases. Using AutoDock Vina, the docking affinities of various compounds for target enzymes were initially screened, revealing 12 bioactive compounds with higher affinities for the target enzymes compared to Avibactam and Tazobactam. Top-scoring metabolites, including Oleanolic acid, Protocatechuic acid, and Tannin, were subjected to MD simulation studies to further analyze the stability of the docked complexes using WebGro. The simulation coordinates, in terms of RMSD, RMSF, SASA, Rg, and hydrogen bonds formed, showed that these phytocompounds are stable enough to retain in the active sites at various orientations. The PCA and FEL analysis also showed the stability of the dynamic motion of Cα residues of phytochemical-bound enzymes. The pharmacokinetic analysis of the top phytochemicals was performed to analyze their bioavailability and toxicity. This study provides new insights into the therapeutic potential of phytochemicals of selected dry fruits and contributes to future experimental studies to identify βL inhibitors from plants.Communicated by Ramaswamy H. Sarma.