Addressing the Metabolic Stability of Antituberculars through Machine Learning

Thomas P. Stratton, Alexander L. Perryman, Catherine Vilchèze, Riccardo Russo, Shao Gang Li, Jimmy S. Patel, Eric Singleton, Sean Ekins, Nancy Connell, William R. Jacobs, Joel S. Freundlich

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


We present the first prospective application of our mouse liver microsomal (MLM) stability Bayesian model. CD117, an antitubercular thienopyrimidine tool compound that suffers from metabolic instability (MLM t1/2 < 1 min), was utilized to assess the predictive power of our new MLM stability model. The S-substituent was removed, a set of commercial reagents was utilized to construct a virtual library of 411 analogues, and our MLM stability model was applied to prioritize 13 analogues for synthesis and biological profiling. In MLM stability assays, all 13 analogues had superior metabolic stability to the parent compound, and six new analogues had acceptable MLM t1/2 values greater than or equal to 60 min. It is noteworthy that whole-cell efficacy and lack of relative mammalian cell cytotoxicity could not be predicted simultaneously. These results support the utility of our new MLM stability model in chemical tool and drug discovery optimization efforts.

Original languageEnglish (US)
Pages (from-to)1099-1104
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number10
StatePublished - Oct 12 2017


  • Bayesian
  • antitubercular
  • chemical tool optimization
  • computer-aided analogue design
  • machine learning
  • mouse liver microsomal stability

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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