Jump to main content
Jump to site search

Issue 11, 2010
Previous Article Next Article

Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis

Author affiliations

Abstract

There is an urgent need for new drugs against tuberculosis which annually claims 1.7–1.8 million lives. One approach to identify potential leads is to screen in vitro small molecules against Mycobacterium tuberculosis (Mtb). Until recently there was no central repository to collect information on compounds screened. Consequently, it has been difficult to analyze molecular properties of compounds that inhibit the growth of Mtbin vitro. We have collected data from publically available sources on over 300 000 small molecules deposited in the Collaborative Drug Discovery TB Database. A cheminformatics analysis on these compounds indicates that inhibitors of the growth of Mtb have statistically higher mean logP, rule of 5 alerts, while also having lower HBD count, atom count and lower PSA (ChemAxon descriptors), compared to compounds that are classed as inactive. Additionally, Bayesian models for selecting Mtb active compounds were evaluated with over 100 000 compounds and, they demonstrated 10 fold enrichment over random for the top ranked 600 compounds. This represents a promising approach for finding compounds active against Mtb in whole cells screened under the same in vitro conditions. Various sets of Mtb hit molecules were also examined by various filtering rules used widely in the pharmaceutical industry to identify compounds with potentially reactive moieties. We found differences between the number of compounds flagged by these rules in Mtb datasets, malaria hits, FDA approved drugs and antibiotics. Combining these approaches may enable selection of compounds with increased probability of inhibition of whole cell Mtb activity.

Graphical abstract: Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis

Back to tab navigation

Supplementary files

Publication details

The article was received on 15 Jul 2010, accepted on 13 Aug 2010 and first published on 08 Sep 2010


Article type: Paper
DOI: 10.1039/C0MB00104J
Citation: Mol. BioSyst., 2010,6, 2316-2324
  •   Request permissions

    Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis

    S. Ekins, T. Kaneko, C. A. Lipinski, J. Bradford, K. Dole, A. Spektor, K. Gregory, D. Blondeau, S. Ernst, J. Yang, N. Goncharoff, M. M. Hohman and B. A. Bunin, Mol. BioSyst., 2010, 6, 2316
    DOI: 10.1039/C0MB00104J

Search articles by author

Spotlight

Advertisements