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Cluster-based molecular docking study for in silico identification of novel 6-fluoroquinolones as potential inhibitors against Mycobacterium tuberculosis.

A classical protein sequence alignment and homology modeling strategy were employed 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-FQs binding pockets. The quality of the generated models was initially validated by docking of the co-crystallized 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 pre-built CP ANN 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 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 utilized in establishing novel possible SAR recommendations in the 6-FQs optimization, which could be of great importance in the current anti-mycobacterial hit-to-lead processes.

Link to the published scientific article: http://onlinelibrary.wiley.com/doi/10.1002/jcc.23268/abstract

 


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New findings about the mechanism of membrane transport identified as breaking journal article for Global Medical Discovery Series

The research team of the Laboratory of Chemometrics has publish recently the study on transmembrane domains of a membrane transporter bilitranslocase: "Structural Analysis of a Peptide Fragment of Transmembrane Transporter Protein Bilitranslocas", PLoS one, 2012; 7(6): e38967.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0038967

 

The challenge discussed in the article is to demonstrate that bilitranslocase is able to transport drugs through the cell membrane. The publication attracted the attention of the Target Selection team of Global Medical Discovery Series. They invited the authors to prepare a short summary and published it, along with the link to the original publication, in the Global Medical Discovery [ISSN 1929-8536]:

 

http://globalmedicaldiscovery.com/key-scientific-articles/structural-analysis-of-a-peptide-fragment-of-transmembrane-transporter-protein-bilitranslocase/

 

 

Global Medical Discovery service alerts the scientific community to breaking journal articles considered to be of importance to the drug discovery process. Global Medical Discovery is viewed almost 365,000 times each month by the audience of academic and industrial R&D personnel and it is featured on the intranets of a growing number of the top 40 BioPharmaceutical companies and major academic institutions. For this reason, the a

uthors of the selected publication are especially motivated to continue with the research topic, which was initiated by the collaboration with Sabina Passamonti, Professor at the University of Trieste, and is extended through the inter-regional strategic research project TRANS2CARE.

http://www.trans2care.eu/Sections.aspx?section=452

 

The results obtained so far indicate that bilitranslocase might be an important membrane transporter for antioxidants as well as for nucleotides and nucleosides, and most probably also for certain drugs.

 

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