Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I

Tuberculosis (Edinb). 2017 Mar:103:52-60. doi: 10.1016/ Epub 2017 Jan 20.


There is a shortage of compounds that are directed towards new targets apart from those targeted by the FDA approved drugs used against Mycobacterium tuberculosis. Topoisomerase I (Mttopo I) is an essential mycobacterial enzyme and a promising target in this regard. However, it suffers from a shortage of known inhibitors. We have previously used computational approaches such as homology modeling and docking to propose 38 FDA approved drugs for testing and identified several active molecules. To follow on from this, we now describe the in vitro testing of a library of 639 compounds. These data were used to create machine learning models for Mttopo I which were further validated. The combined Mttopo I Bayesian model had a 5 fold cross validation receiver operator characteristic of 0.74 and sensitivity, specificity and concordance values above 0.76 and was used to select commercially available compounds for testing in vitro. The recently described crystal structure of Mttopo I was also compared with the previously described homology model and then used to dock the Mttopo I actives norclomipramine and imipramine. In summary, we describe our efforts to identify small molecule inhibitors of Mttopo I using a combination of machine learning modeling and docking studies in conjunction with screening of the selected molecules for enzyme inhibition. We demonstrate the experimental inhibition of Mttopo I by small molecule inhibitors and show that the enzyme can be readily targeted for lead molecule development.

Keywords: Bayesian models; Collaborative drug discovery tuberculosis database; Docking; Function class fingerprints; Homology model; Mycobacterium tuberculosis; Topoisomerase; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry
  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology*
  • Bayes Theorem
  • Computer-Aided Design
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Machine Learning*
  • Molecular Docking Simulation*
  • Molecular Targeted Therapy
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium smegmatis / growth & development
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / growth & development
  • Protein Conformation
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / metabolism
  • Topoisomerase I Inhibitors / pharmacology*
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I