Identification of potential drug targets in Yersinia pestis using metabolic pathway analysis: MurE ligase as a case study.
Sporadic outbreaks of plague, lack of a vaccine, emergence of multidrug-resistant strains of Yersinia pestis, and its potential use in bioterrorism, call for an urgent need to develop new drugs for plague. We have used comparative metabolic pathway analysis to identify 245 drug-target candidate enzymes in Y. pestis CO92 which are non-homologous to host Homo sapiens and likely to be essential for the pathogen's survival. Further analysis revealed that 25 of these are potential choke point enzymes. As a case study, structure of a choke point enzyme, MurE ligase, was modeled and docking studies performed against a library of compounds leading to identification of a potential inhibitor. This approach enables rapid potential drug-target identification, thereby facilitating search for new antimicrobials.
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry 605014, India. aditya2088@gmail.com
Aditya
A
Sharma
Archana
A
Pan
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010930:Plague / Q000517:prevention & control; D016415:Sequence Alignment; D054852:Small Molecule Libraries / Q000737:chemistry*; D013045:Species Specificity; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D015010:Yersinia pestis / Q000201:enzymology* / Q000235:genetics
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D008025:Ligases