title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, Howard University, 525 College Street, NW, Washington, DC 20059, United States.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Ogindo
authors.affiliation: Department of Biology, Howard University, 415 College Street, NW, Washington, DC 20059, United States.
authors.forename: Mozna H
authors.initials: MH
authors.lastname: Khraiwesh
authors.affiliation: Department of Biochemistry and Molecular Biology, Howard University, 520 W Street NW, Washington, DC 20059, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: George
authors.affiliation: Department of Chemistry, Howard University, 525 College Street, NW, Washington, DC 20059, United States.
authors.forename: Yakini
authors.initials: Y
authors.lastname: Brandy
authors.affiliation: Department of Chemistry, Howard University, 525 College Street, NW, Washington, DC 20059, United States.
authors.forename: Nailah
authors.initials: N
authors.lastname: Brandy
authors.affiliation: Department of Biology, Howard University, 415 College Street, NW, Washington, DC 20059, United States.
authors.forename: Ayele
authors.initials: A
authors.lastname: Gugssa
authors.affiliation: Department of Comprehensive Sciences, Howard University, 260 Locker Hall Street, NW, Washington, DC 20059, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ashraf
authors.affiliation: Department of Microbiology, Howard University, 520 W Street NW, Washington, DC 20059, United States; The National Human Genome Center, Howard University, 2041 Georgia Avenue NW, Washington, DC 20060, United States.
authors.forename: Muneer
authors.initials: M
authors.lastname: Abbas
authors.affiliation: Department of Biochemistry and Molecular Biology, Howard University, 520 W Street NW, Washington, DC 20059, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Southerland
authors.affiliation: Department of Biology, Howard University, 415 College Street, NW, Washington, DC 20059, United States.
authors.forename: Clarence M
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Howard University, 525 College Street, NW, Washington, DC 20059, United States.
authors.forename: Oladapo
authors.initials: O
authors.lastname: Bakare
authors.affiliation: Department of Biochemistry and Molecular Biology, Howard University, 520 W Street NW, Washington, DC 20059, United States.
authors.forename: Yayin
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000595:Amino Acid Sequence; D014355:Chagas Disease / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D058105:Polymerization; D017386:Sequence Homology, Amino Acid; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
chemical_list: D014344:Trypanocidal Agents; D014404:Tubulin
keywords: Binding site prediction; Chagas disease; Homology modeling; Naphthoquinone derivatives; Structure based drug design (SBDD); Trypanosoma cruzi; Tubulin polymerization inhibition