Virtual High-Throughput Screening of Carbapenem Derivatives as New Generation Carbapenemase and Penicillin Binding Protein Inhibitors: A Hunt to Save Drug of Last Resort.

Virtual High-Throughput Screening of Carbapenem Derivatives as New Generation Carbapenemase and Penicillin Binding Protein Inhibitors: A Hunt to Save Drug of Last Resort. Comb Chem High Throughput Screen. 2014 Dec 26; Authors: Chowdhury A, Paul P, Bhattacharjee A, Talukdar AD, Choudhury MD 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 hypotheses 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 unwanted hydrolysis of available drugs. In this work, over thousands 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 obeyed the first hypothesis and rest obeyed the second. Ligand L5 strictly followed the first hypothesis completely and L1-L4 obeyed to a satisfactory level. Molecular dynamic simulation was performed to check post-docking stability of the pharmacophores. PMID: 25542226 [PubMed - as supplied by publisher]
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research