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  • Cluster-based molecular docking study for in silico identification of novel 6-fluoroquinolones as potential inhibitors against mycobacterium tuberculosis
    Minovski, Nikola ...
    A classical protein sequence alignment and homology modeling strategy were used for building three Mycobacterium tuberculosis-DNA gyrase protein models using the available topoII-DNA-6FQ crystal ... structure complexes originating from different organisms. The recently determined M. tuberculosis-DNA gyrase apoprotein structures and topoII-DNA-6FQ complexes were used for defining the 6-fluoroquinolones (6-FQs) binding pockets. The quality of the generated models was initially validated by docking of the cocrystallized ligands into their binding site, and subsequently by quantitative evaluation of their discriminatory performances (identification of active/inactive 6-FQs) for a set of 145 6-FQs with known biological activity values. The M. tuberculosis-DNA gyrase model with the highest estimated discriminatory power was selected and used afterwards in an additional molecular docking experimenton a mixed combinatorial set of 427 drug-like 6-FQ analogs for which the biological activity values were predicted using a prebuilt counter-propagation artificial neural network model. A novel three-level Boolean-based [T/F (true/false)] clustering algorithm was used to assess the generated binding poses: Level 1 (geometry properties assessment), Level 2 (score-based clustering and selection of the (T)-signed highly scored Level 1 poses), and Level 3 (activity-based clustering and selection of the most ĆactiveĆ (T)-signed Level 2 hits). The frequency analysis of occurrence of the fragments attached at R1 and R7 position of the (T)-signed 6-FQs selected in Level 3 revealed several novel attractive fragments and confirmed some previous findings. We believe that this methodology could be successfully usedin establishing novel possible structure-activity relationship recommendations in the 6-FQs optimization, which could be of great importance in the current antimycobacterial hit-to-lead processes.
    Vir: Journal of computational chemistry. - ISSN 0192-8651 (Vol. 34, no. 9, 2013, str. 790-801)
    Vrsta gradiva - članek, sestavni del
    Leto - 2013
    Jezik - angleški
    COBISS.SI-ID - 5145626
    DOI

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