Discovery of novel MDR-Mycobacterium tuberculosis inhibitor by new FRIGATE computational screen

With 1.6 million casualties annually and 2 billion people being infected, tuberculosis is still one of the most pressing healthcare challenges. Here we report on the new computational docking algorithm FRIGATE which unites continuous local optimization techniques (conjugate gradient method) with an...

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Bibliographic Details
Published inPloS one Vol. 6; no. 12; p. e28428
Main Authors Scheich, Christoph, Szabadka, Zoltán, Vértessy, Beáta, Pütter, Vera, Grolmusz, Vince, Schade, Markus
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 02.12.2011
Public Library of Science (PLoS)
Subjects
Adenosine
Algorithms
Antigens
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Bacterial Proteins - chemistry
Binding Sites
Biology
Biosynthesis
Casualties
Catalysis
Catalytic Domain
Chemistry
Chemistry, Pharmaceutical - methods
Computation
Computational Biology - methods
Computer applications
Computer science
Conjugate gradient method
Cytotoxicity
Docking
Drug Design
Drug resistance
Energy
Enzymes
Frigates
Health care
Ligands
Local optimization
Magnetic Resonance Spectroscopy - methods
Medicine
Models, Molecular
Molecular Conformation
Multidrug resistance
Mycobacterium smegmatis
Mycobacterium tuberculosis
Mycobacterium tuberculosis - metabolism
Optimization
Optimization theory
Protein Binding
Proteins
Reproducibility of Results
Software
Tuberculosis
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
Zinc
Hungary
Germany
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Summary:With 1.6 million casualties annually and 2 billion people being infected, tuberculosis is still one of the most pressing healthcare challenges. Here we report on the new computational docking algorithm FRIGATE which unites continuous local optimization techniques (conjugate gradient method) with an inherently discrete computational approach in forcefield computation, resulting in equal or better scoring accuracies than several benchmark docking programs. By utilizing FRIGATE for a virtual screen of the ZINC library against the Mycobacterium tuberculosis (Mtb) enzyme antigen 85C, we identified novel small molecule inhibitors of multiple drug-resistant Mtb, which bind in vitro to the catalytic site of antigen 85C.
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Conceived and designed the experiments: CS ZS BV VP VG MS. Performed the experiments: CS ZS VP VG MS. Analyzed the data: CS ZS BV VP VG MS. Contributed reagents/materials/analysis tools: CS ZS VP VG MS. Wrote the paper: CS ZS BV VG MS.
Current address: Evotec AG, Hamburg, Germany
Current address: Bayer Schering Pharma AG, Berlin, Germany
Current address: AstraZeneca Ltd, DS Biophysics, Macclesfield, United Kingdom
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0028428