Target Identification of <i>Mycobacterium tuberculosis</i> Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach.

ABSTRACT: Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC₅₀ below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed us

SUBMITTER: Mugumbate G 

PROVIDER: S-EPMC5623190 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature