Pharmaceutical Research

, Volume 29, Issue 8, pp 2115–2127

Combining Cheminformatics Methods and Pathway Analysis to Identify Molecules with Whole-Cell Activity Against Mycobacterium Tuberculosis

  • Malabika Sarker
  • Carolyn Talcott
  • Peter Madrid
  • Sidharth Chopra
  • Barry A. Bunin
  • Gyanu Lamichhane
  • Joel S. Freundlich
  • Sean Ekins
Research Paper

Abstract

Purpose

New strategies for developing inhibitors of Mycobacterium tuberculosis (Mtb) are required in order to identify the next generation of tuberculosis (TB) drugs. Our approach leverages the integration of intensive data mining and curation and computational approaches, including cheminformatics combined with bioinformatics, to suggest biological targets and their small molecule modulators.

Methods

We now describe an approach that uses the TBCyc pathway and genome database, the Collaborative Drug Discovery database of molecules with activity against Mtb and their associated targets, a 3D pharmacophore approach and Bayesian models of TB activity in order to select pathways and metabolites and ultimately prioritize molecules that may be acting as substrate mimics and exhibit activity against TB.

Results

In this study we combined the TB cheminformatics and pathways databases that enabled us to computationally search >80,000 vendor available molecules and ultimately test 23 compounds in vitro that resulted in two compounds (N-(2-furylmethyl)-N′-[(5-nitro-3-thienyl)carbonyl]thiourea and N-[(5-nitro-3-thienyl)carbonyl]-N′-(2-thienylmethyl)thiourea) proposed as mimics of D-fructose 1,6 bisphosphate, (MIC of 20 and 40 μg/ml, respectively).

Conclusion

This is a simple yet novel approach that has the potential to identify inhibitors of bacterial growth as illustrated by compounds identified in this study that have activity against Mtb.

Key Words

Bioinformatics cheminformatics Collaborative drug discovery Mycobacterium tuberculosis pharmacophore 

Supplementary material

11095_2012_741_MOESM1_ESM.xls (1.1 mb)
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11095_2012_741_MOESM2_ESM.csv (91 kb)
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11095_2012_741_MOESM3_ESM.xlsx (26 kb)
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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Malabika Sarker
    • 1
  • Carolyn Talcott
    • 1
  • Peter Madrid
    • 1
  • Sidharth Chopra
    • 1
  • Barry A. Bunin
    • 2
  • Gyanu Lamichhane
    • 3
  • Joel S. Freundlich
    • 4
  • Sean Ekins
    • 2
    • 5
  1. 1.SRI InternationalMenlo ParkUSA
  2. 2.Collaborative Drug DiscoveryBurlingameUSA
  3. 3.Department of MedicineJohns Hopkins School of MedicineBaltimoreUSA
  4. 4.Departments of Pharmacology & Physiology and MedicineCenter for Emerging and Reemerging Pathogens, UMDNJ—New Jersey Medical SchoolNewarkUSA
  5. 5.Collaborations in ChemistryFuquay-VarinaUSA

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