Document Detail

A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910.
MedLine Citation:
PMID:  17387738     Owner:  NLM     Status:  MEDLINE    
Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.
Marc R de Jonge; Luc H M Koymans; Jérôme E G Guillemont; Anil Koul; Koen Andries
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Proteins     Volume:  67     ISSN:  1097-0134     ISO Abbreviation:  Proteins     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-05-11     Completed Date:  2007-06-07     Revised Date:  2013-04-10    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  United States    
Other Details:
Languages:  eng     Pagination:  971-80     Citation Subset:  IM    
Copyright Information:
2007 Wiley-Liss, Inc.
MolMo Services BVBA, Campus Blairon 424, B2300 Turnhout, Belgium.
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MeSH Terms
Adenosine Triphosphatases / antagonists & inhibitors*,  chemistry,  metabolism*
Amino Acid Sequence
Binding Sites
Computer Simulation*
Enzyme Inhibitors / chemistry*,  pharmacology*
Models, Molecular
Molecular Sequence Data
Mycobacterium tuberculosis / enzymology*
Protein Binding
Protein Folding
Protein Structure, Quaternary
Protein Subunits / chemistry,  metabolism
Quinolines / chemistry*,  pharmacology*
Sequence Alignment
Sequence Homology, Amino Acid
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Protein Subunits; 0/Quinolines; 458-24-2/Fenfluramine; 78846I289Y/Bedaquiline; EC 3.6.1.-/Adenosine Triphosphatases

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