Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives

[Display omitted] Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the ru...

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Published in:	Bioorganic & medicinal chemistry Vol. 24; no. 16; pp. 3849 - 3855
Main Authors:	Ogindo, Charles O., Khraiwesh, Mozna H., George, Matthew, Brandy, Yakini, Brandy, Nailah, Gugssa, Ayele, Ashraf, Mohammad, Abbas, Muneer, Southerland, William M., Lee, Clarence M., Bakare, Oladapo, Fang, Yayin
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-08-2016
Subjects:	Amino Acid Sequence Binding site prediction Chagas disease Chagas Disease - drug therapy Drug Design Homology modeling Humans Naphthoquinone derivatives Polymerization Sequence Homology, Amino Acid Structure based drug design (SBDD) Trypanocidal Agents - chemistry Trypanocidal Agents - pharmacology Trypanocidal Agents - therapeutic use Trypanosoma cruzi Trypanosoma cruzi - drug effects Tubulin - chemistry Tubulin - drug effects Tubulin - metabolism Tubulin polymerization inhibition Tubulin polymerization inhibition Homology modeling Chagas disease Naphthoquinone derivatives Binding site prediction Structure based drug design (SBDD) Trypanosoma cruzi
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Summary:	[Display omitted] Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson’s r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2016.06.031