Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I

Ekins, Sean and Godbole, Adwait Anand and Keri, Gyorgy and Orfi, Laszlo and Pato, Janos and Bhat, Rajeshwari Subray and Verma, Rinkee and Bradley, Erin K and Nagaraja, Valakunja (2017) Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I. In: TUBERCULOSIS, 103 . pp. 52-60.

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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. (C) 2017 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Publication:	TUBERCULOSIS
Additional Information:	Copy right for this article belongs to the CHURCHILL LIVINGSTONE, JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	20 May 2017 03:49
Last Modified:	25 Feb 2019 12:38
URI:	http://eprints.iisc.ac.in/id/eprint/56690

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