A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans

Andrew R. Burns, Iain M. Wallace, Jan Wildenhain, Mike Tyers, Guri Giaever, Gary D. Bader, Corey Nislow, Sean R. Cutler, Peter J. Roy

Research output: Contribution to journalArticlepeer-review

Abstract

The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn which structures evade the worm's defenses, we performed the first survey of the accumulation and metabolism of over 1,000 commercially available drug-like small molecules in the worm. We discovered that fewer than 10% of these molecules accumulate to concentrations greater than 50% of that present in the worm's environment. Using our dataset, we developed a structure-based accumulation model that identifies compounds with an increased likelihood of bioavailability and bioactivity, and we describe structural features that facilitate small-molecule accumulation in the worm. Preselecting molecules that are more likely to reach a target by first applying our model to the tens of millions of commercially available compounds will undoubtedly increase the success of future small-molecule screens with C. elegans.

Original languageEnglish
Pages (from-to)549-557
Number of pages9
JournalNature Chemical Biology
Volume6
Issue number7
Early online date30 May 2010
DOIs
Publication statusPublished - 31 Jul 2010

Keywords

  • Drug screening
  • Molecular modelling
  • Pharmacokinetics
  • Small molecules

Fingerprint

Dive into the research topics of 'A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans'. Together they form a unique fingerprint.

Cite this