title: Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum β-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium that frequently causes nosocomial infections. New generation cephalosporins and β-lactams along with inhibitors are used for the treatment of opportunistic bacterial infections. The indiscriminate use of antibiotics has led to the emergence of bacterial resistance. Carbapenem class of antibiotics like imipenem and meropenem are currently the final line of antibiotics for the treatment of infections caused by multidrug-resistant P. aeruginosa. Recent reports indicate that P. aeruginosa has acquired resistance to imipenem through a class D oxacillinase-OXA-10 extended spectrum β-lactamase (ESBL). OXA-10 ESBL is encoded by the gene blaOXA-10. There is an urgent need to develop OXA-10 ESBL non-hydrolysing inhibitors. We have attempted to locate OXA-10 ESBL inhibitors by performing molecular docking and molecular dynamics studies on OXA-10 ESBL with imipenem analogues from ZINC database as well as employing imipenem to understand the mechanism of resistance at the structural level. Our in-silico analysis of imipenem analogues reveals that ZINC44672480 has ideal characteristics for a potent OXA-10 ESBL non-hydrolysing inhibitor. We believe that the results from our study will provide valuable insights into the mechanism of drug resistance and aid in designing potent inhibitors against OXA-10 ESBL producing P. aeruginosa.
authors.affiliation: Medical & Biological Computing Laboratory, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India.
authors.forename: Kullappan
authors.initials: K
authors.lastname: Malathi
authors.affiliation: Medical & Biological Computing Laboratory, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India. sudhaanand@vit.ac.in.
authors.forename: Sudha
authors.initials: S
authors.lastname: Ramaiah
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology*; D012399:Rotation; D013816:Thermodynamics; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C055187:beta-lactamase PSE-2; D001618:beta-Lactamases
keywords: Analogues; Drug-likeness; Resistance; Toxicity; β-Lactamase