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Pharmacophore identification and virtual screening for methionyl-tRNA synthetase inhibitors   
摘  要:   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 istodiscovernewlead moleculeswhichwouldbeuseful asanti-bacterialcompounds.Pharmacophoremodelsweredevelopedbyusing CATALYST HypoGen with a training set of 29 diverse methionyl-tRNA synthetase (MetRS) inhibitors. The best quantitative pharmacophore hypothesis (Hypo1) 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 Hypo1 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 forscreening databasesfor discoveryof new MetRSinhibitors.The newlead compounds werefurther analyzedfor drug-likeproperties.Homology modeled structure of Staphylococcus aureusMetRS 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.
发  表:   Journal of Molecular Graphics and Modelling  2007

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