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Published on: October 25, 2019
Identification of potential drug targets in Yersinia pestis using metabolic pathway analysis: MurE ligase as a case
1Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry 605014, India. aditya2088@gmail.com
Abstract:
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.
Insights
New plague drugs are urgently needed due to resistant strains and bioterrorism threats. A computational approach identified essential Yersinia pestis drug targets, including choke point enzymes like MurE ligase, leading to a potential inhibitor discovery.
Area of Science:
- Microbiology
- Drug Discovery
- Computational Biology
Background:
- Plague outbreaks, lack of vaccines, and drug-resistant Yersinia pestis strains necessitate novel antimicrobial development.
- The potential for Yersinia pestis to be used in bioterrorism further underscores the urgent need for new therapeutic strategies.
Purpose of the Study:
- To identify essential drug-target candidate enzymes in Yersinia pestis CO92 using comparative metabolic pathway analysis.
- To pinpoint potential choke point enzymes crucial for pathogen survival and non-homologous to human enzymes.
- To demonstrate a case study for rapid drug-target identification and inhibitor discovery.
Main Methods:
- Comparative metabolic pathway analysis of Yersinia pestis CO92.
- Identification of non-homologous and essential enzymes.
- Structural modeling of choke point enzymes, specifically MurE ligase.
- Molecular docking studies against compound libraries.
Main Results:
- Identified 245 potential drug-target candidate enzymes in Y. pestis CO92.
- Further analysis revealed 25 potential choke point enzymes.
- Modeled the structure of MurE ligase and performed docking studies.
- Identified a potential inhibitor for the MurE ligase choke point enzyme.
Conclusions:
- Comparative metabolic pathway analysis is an effective strategy for identifying essential drug targets in Yersinia pestis.
- The identified choke point enzymes, such as MurE ligase, represent promising targets for novel antimicrobial drug development.
- This computational approach facilitates the rapid identification of potential drug targets and inhibitors for plague treatment.
