Molecular docking and simulation studies of outer membrane proteins with piperacillin; a broad-spectrum antibiotic against <i>Pseudomonas aeruginosa</i>

One of the most important public health concerns is the rise of the multi-drug resistance bacteria in the recent years. <i>Pseudomonas aeruginosa</i> is a frequent Gram-negative bacterium prominent in the hospital-acquired illness and is considered as an opportunistic human pathogen responsible for causing nosocomial infections. Numerous burn victims, cystic fibrosis patients, and those with neutropenic malignancy die as a result of it. The current approach involves molecular docking for the predominant recognition of the drug binding site for the designing of the potent inhibitors for inhibiting the membrane protein of <i>Pseudomonas aeruginosa</i>. The present study has targeted 11 outer membrane proteins of <i>Pseudomonas aeruginosa</i> with 12 different FDA approved drugs. Protein modeling has been applied to create the target proteins. As per the results revealed out from the docking perspective, Piperacillin which has been categorized under the broad-spectrum antibiotics has emerged out as one of the forerunners as compared to the other group of antibiotics as it exhibited highest binding energy, i.e. -10.4 kcal/mol. Hence, the compound has been validated using <i>in-silico</i> tools such as ADME and PROTOX-II server which indicates its nontoxic nature. Molecular dynamics simulations were conducted for EGCG-OprP, Piperacillin-OprB, OprP (Apoprotein), and OprB (Apoprotein) complexes to assess their binding efficacy. Statistical parameters such as RMSD, RMSF, h-bond interactions, and % occupancies indicated stability in ligand binding. Protein RMSD values plateaued at approximately 0.5 nm, while ligand RMSD values remained below 0.2 nm, affirming stability in binding OprP and OprB. H-bond analysis revealed stable contacts for EGCG and Piperacillin, and % occupancies indicated specific interactions. Energetics analysis yielded deltaG values of -30.45 for EGCG and -56.66 for Piperacillin, suggesting efficient binding with OprP and OprB. This positioned Piperacillin as a promising candidate for future pharmacological studies, considering its classification as a broad-spectrum antibiotic against P. aeruginosa. The study served as a crucial roadmap for designing drugs to inhibit this formidable pathogen amid rising antibiotic resistance, emphasizing its significance in the ongoing battle against infectious diseases.