Exploring novel antimicrobials targeting bacterial pyruvate formate lyase through pharmacophore based virtual screening

Abstract

Antibiotic resistance has caused a serious impediment in clinical treatment of bacterial infections. This resistance is developed by the micro-organisms over a specific time interval during which the microbes develop or modify metabolic machineries that cause immunity towards the antimicrobial agents, like the development of antibodies in eukaryotes. Thus, development of new antimicrobials, targeting bacterial metabolic pathways not being touched before, is the only solution to fight against drug resistance bacteria. The current project has attempted to explore novel anti-bacterial that act against Pyruvate formate lyase (PFL), an essential enzyme for bacterial survival, using computational methods. PFL couples glycolytic pathway to Krebs’s cycle by converting Pyruvate to Acetyl CoA so that the latter is utilized for ATPs production. Inhibition of PFL leads to energy shutdown in a bacterial cell. To find novel inhibitors of PFL, a structure based pharmacophore consisting of seven chemical features was used to screen a number of databases. Phytochemical (8856 compounds) and PubChem (61967 compounds) databases showed good scoring. A total of 183 drug candidates were selected and further processed by molecular docking and rescoring programs in AutoDock Vina. The 17 binding energy based shortlisted drug candidates were predicted for their toxicity and drug likeness in AdmetSAR tool. The docked poses were visually analyzed for bonding interactions between the ligand-receptor pair in LIGPLOT. The docked poses, one from Phytochemical and five from PubChem databases, showed a good pharmacophore fit score of range of 88.4 to 85.81 and a high binding energy efficiency of less than 6.0 kJ/mol. All the six ligands also passed the drug toxicity and likeness criteria set by ADMET tool. LIGPLOT analysis of the compound further confirmed good interaction with the binding pocket residues Lys600, Asp 661, Gln 428 and Gln 430.