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Combining cheminformatics methods and pathway analysis to identify molecules with whole-cell activity against Mycobacterium tuberculosis.
Pharm Res. 2012 Aug; 29(8):2115-27.PR

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.

Authors+Show Affiliations

SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22477069

Citation

Sarker, Malabika, et al. "Combining Cheminformatics Methods and Pathway Analysis to Identify Molecules With Whole-cell Activity Against Mycobacterium Tuberculosis." Pharmaceutical Research, vol. 29, no. 8, 2012, pp. 2115-27.
Sarker M, Talcott C, Madrid P, et al. Combining cheminformatics methods and pathway analysis to identify molecules with whole-cell activity against Mycobacterium tuberculosis. Pharm Res. 2012;29(8):2115-27.
Sarker, M., Talcott, C., Madrid, P., Chopra, S., Bunin, B. A., Lamichhane, G., Freundlich, J. S., & Ekins, S. (2012). Combining cheminformatics methods and pathway analysis to identify molecules with whole-cell activity against Mycobacterium tuberculosis. Pharmaceutical Research, 29(8), 2115-27. https://doi.org/10.1007/s11095-012-0741-5
Sarker M, et al. Combining Cheminformatics Methods and Pathway Analysis to Identify Molecules With Whole-cell Activity Against Mycobacterium Tuberculosis. Pharm Res. 2012;29(8):2115-27. PubMed PMID: 22477069.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combining cheminformatics methods and pathway analysis to identify molecules with whole-cell activity against Mycobacterium tuberculosis. AU - Sarker,Malabika, AU - Talcott,Carolyn, AU - Madrid,Peter, AU - Chopra,Sidharth, AU - Bunin,Barry A, AU - Lamichhane,Gyanu, AU - Freundlich,Joel S, AU - Ekins,Sean, Y1 - 2012/04/04/ PY - 2011/08/31/received PY - 2012/03/16/accepted PY - 2012/4/6/entrez PY - 2012/4/6/pubmed PY - 2012/12/10/medline SP - 2115 EP - 27 JF - Pharmaceutical research JO - Pharm. Res. VL - 29 IS - 8 N2 - 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. SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/22477069/Combining_cheminformatics_methods_and_pathway_analysis_to_identify_molecules_with_whole_cell_activity_against_Mycobacterium_tuberculosis_ L2 - https://doi.org/10.1007/s11095-012-0741-5 DB - PRIME DP - Unbound Medicine ER -