Drug discovery using chemical systems biology: Repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis

Sarah L. Kinnings, Nina Liu, Nancy Buchmeier, Peter J. Tonge, Lei Xie, Philip E. Bourne

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 mM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 mM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs.

Original languageEnglish (US)
Article numbere1000423
JournalPLoS Computational Biology
Volume5
Issue number7
DOIs
StatePublished - Jul 2009
Externally publishedYes

Fingerprint

Extensively Drug-Resistant Tuberculosis
Drug Discovery
Tuberculosis
tuberculosis
Systems Biology
medicine
Medicine
Assays
Drugs
drug
Lead compounds
Biological Sciences
drugs
Kinetics
Cytotoxicity
Pharmaceutical Preparations
Drug products
Toxicity
Enzymes
Pipelines

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Drug discovery using chemical systems biology : Repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. / Kinnings, Sarah L.; Liu, Nina; Buchmeier, Nancy; Tonge, Peter J.; Xie, Lei; Bourne, Philip E.

In: PLoS Computational Biology, Vol. 5, No. 7, e1000423, 07.2009.

Research output: Contribution to journalArticle

Kinnings, Sarah L. ; Liu, Nina ; Buchmeier, Nancy ; Tonge, Peter J. ; Xie, Lei ; Bourne, Philip E. / Drug discovery using chemical systems biology : Repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. In: PLoS Computational Biology. 2009 ; Vol. 5, No. 7.
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