Document Detail


Cluster-based molecular docking study for in silico identification of novel 6-fluoroquinolones as potential inhibitors against mycobacterium tuberculosis.
MedLine Citation:
PMID:  23280926     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 experiment on 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 "active" (T)-signed Level 2 hits). The frequency analysis of occurrence of the fragments attached at R(1) and R(7) 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 used in 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. © 2012 Wiley Periodicals, Inc.
Authors:
Nikola Minovski; Andrej Perdih; Marjana Novic; Tom Solmajer
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-19
Journal Detail:
Title:  Journal of computational chemistry     Volume:  -     ISSN:  1096-987X     ISO Abbreviation:  J Comput Chem     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-1-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9878362     Medline TA:  J Comput Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. nikola.minovski@ki.si.
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