Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I.

Journal: Tuberculosis (Edinburgh, Scotland)
Published Date: Mar 1, 2017

Abstract

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.

Authors

  • Sean Ekins
    Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA; Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010, USA; Collaborations Pharmaceuticals, Inc., 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA; Phoenix Nest, Inc., P.O. Box 150057, Brooklyn, NY 11215, USA; Hereditary Neuropathy Foundation, 401 Park Avenue South, 10th Floor, New York, NY 10016, USA. Electronic address: ekinssean@yahoo.com.
  • Adwait Anand Godbole
    Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
  • György Kéri
    Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022, Budapest, Hungary; Semmelweis Univ, Dept Med Chem, MTA SE Pathobiochem Res Grp, H-1092, Budapest, Hungary.
  • Lászlo Orfi
    Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022, Budapest, Hungary; Semmelweis Univ, Dept Med Chem, MTA SE Pathobiochem Res Grp, H-1092, Budapest, Hungary.
  • János Pato
    Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022, Budapest, Hungary.
  • Rajeshwari Subray Bhat
    Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
  • Rinkee Verma
    Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
  • Erin K Bradley
    LigDCipher, 729 Nevada Ave, San Mateo, CA 94402, USA.
  • Valakunja Nagaraja
    Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India. Electronic address: vraj@mcbl.iisc.ernet.in.

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