Release of 50 New, Drug-Like Compounds and Their Computational Target Predictions for Open Source Anti-Tubercular Drug Discovery

PLoS One. 2015 Dec 7;10(12):e0142293. doi: 10.1371/journal.pone.0142293. eCollection 2015.

Abstract

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antitubercular Agents / pharmacology*
  • Cell Line, Tumor
  • Computational Biology / methods
  • Drug Design
  • Drug Discovery / methods
  • Hep G2 Cells
  • Humans
  • Mycobacterium tuberculosis / drug effects*

Substances

  • Antitubercular Agents

Associated data

  • Dryad/10.5061/dryad.8R351

Grant support

The research behind these results received funding from the TB Alliance, the European Union’s 7th framework programme (FP7-2007–2013) under grant agreement ORCHID no. 261378 and the ERA-NET Pathogenomics Project GeMoA (PIM2010EPA-00719). Those funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder GlaxoSmithKline provided support in the form of salaries for authors [MJR, JL, DAG, JCP, GC, VB, RJY, MMH, RGR, RHB, EMLR, AML, JRB, EAR, NC. LB and DBA], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.