Footprinting of Inhibitor Interactions of In Silico Identified Inhibitors of Trypanothione Reductase of Leishmania Parasite

Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) from Leishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Cluste...

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Bibliographic Details
Published in:TheScientificWorld 2012-01, Vol.2012 (2012), p.1-13
Main Authors: Venkatesan, Santhosh K., Dubey, Vikash Kumar
Format: Article
Language:English
Subjects:
Alkaloids
Animals
Automation
Bacterial proteins
Binding
Binding sites
Clustering
Computational chemistry
Docking
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzymes
Footprinting
Genetic algorithms
Health aspects
Inhibitors
Kinetics
Leishmania
Leishmania - enzymology
Leishmania infantum
Ligands
Microbiological research
Models, Molecular
Molecular chains
Multiculturalism & pluralism
NADH, NADPH Oxidoreductases - antagonists & inhibitors
Parasites
Parasitic diseases
Pharmaceutical sciences
Protein research
Protein-protein interactions
Proteins
Screening
Software
Tropical diseases
Trypanothione
Trypanothione reductase
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Summary:Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) from Leishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Clustering of hits yielded four major clusters each comprising varying number of subclusters differing in their mode of binding and orientation in the active site. Moreover, for the first time, we report selected alkaloids and dibenzothiazepines as inhibitors of Leishmania infantum TR. The mode of binding observed among the clusters also potentiates the probable in vitro inhibition kinetics and aids in defining key interaction which might contribute to the inhibition of enzymatic reduction of T[S] 2. The method provides scope for automation and integration into the virtual screening process employing docking softwares, for clustering the small molecule inhibitors based upon protein-ligand interactions.
ISSN:2356-6140
1537-744X
1537-744X
DOI:10.1100/2012/963658