Pharmacophore identification and virtual screening for methionyl-tRNA synthetase inhibitors

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes involved in protein biosynthesis in all living organisms and are an unexploited antibacterial targets, as many strains of bacteria have become resistant to all established classes of antibiotics. Therefore, the main aim of this study is to discover new lead molecules which would be useful as anti-bacterial compounds. Pharmacophore models were developed by using CATALYST HypoGen with a training set of 29 diverse methionyl-tRNA synthetase (MetRS) inhibitors. The best quantitative pharmacophore hypothesis (Hypo I) obtained a correlation coefficient of 0.975, root mean square deviation (RMSD) of 0.55 and cost difference (null cost-total cost) of 70.32. This Hypo I was validated by two methods, first by using 104 test set molecules which resulted a correlation of 0.926 between HypoGen estimated activities versus experimental activities and secondly by Cat-Scramble validation method. This validated pharmacophore model was further used for screening databases for discovery of new MetRS inhibitors. The new lead compounds were further analyzed for drug-like properties. Homology modeled structure of Staphylococcus aureus MetRS was built and molecular docking studies were performed with many inhibitors using the newly built protein structure. Finally, it was found that the new leads exhibited good estimated inhibitory activity, calculated binding properties similar to experimentally proven compounds and also favorable drug-like properties. (c) 2006 Elsevier Inc. All rights reserved.