title: Virtual high throughput screening of carbapenem derivatives as new generation carbapenemase and penicillin binding protein inhibitors: a hunt to save drug of last resort.
abstract: The advent of carbapenem resistance by the production of β-lectamases and mutated penicillin binding proteins (PBPs) has challenged the treatment of Enterobacteriaceae. Hence there is an urgent need to establish drugs that can fit in the pipeline by overcoming those situations. The working hypothesis of the work is based on two facts, i.e., i) design of inhibitors against mutated PBPs to which present drugs cannot bind efficiently to kill pathogen by inhibiting cell wall formation, ii) design of molecules that can bind with β-lectamases with high affinity, so that they can supplement available drugs preventing their unwanted hydrolysis. In this work, over thousands of thienamycin (first natural carbapenem) derivatives were generated and out of which non-toxic 273 molecules were used for further study. Out of which, only few followed the first hypothesis and rest obeyed the second. Ligand L5 strictly followed the first hypothesis and L1-L4 followed to a satisfactory level. Molecular dynamic simulation was performed to check post-docking stability of the pharmacophores.
authors.affiliation: Department of Life Science & Bioinformatics, Assam University Silchar, Cachar, Assam, India. abhishek@bioinfoaus.ac.in
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chowdhury
authors.forename: Paulomi
authors.initials: P
authors.lastname: Paul
authors.forename: Amitabha
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Anupam Das
authors.initials: AD
authors.lastname: Talukdar
authors.forename: Manabendra Dutta
authors.initials: MD
authors.lastname: Choudhury
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015780:Carbapenems / Q000737:chemistry* / Q000494:pharmacology; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007711:Klebsiella pneumoniae / Q000201:enzymology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D004791:Enzyme Inhibitors; D046915:Penicillin-Binding Proteins; D001618:beta-Lactamases; C063912:carbapenemase