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ACS Med Chem Lett. 2017 Sep 14;8(10):1099-1104. doi: 10.1021/acsmedchemlett.7b00299. eCollection 2017.

Addressing the Metabolic Stability of Antituberculars through Machine Learning.

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  • 1Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey 07103, United States.
  • 2Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
  • 3Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, New Jersey 07103, United States.
  • 4Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, California 94010, United States.
  • 5Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.


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.


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

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