title: A computational analysis of the binding mode of closantel as inhibitor of the Onchocerca volvulus chitinase: insights on macrofilaricidal drug design.
abstract: Onchocerciasis is a leading cause of blindness with at least 37 million people infected and more than 120 million people at risk of contracting the disease; most (99%) of this population, threatened by infection, live in Africa. The drug of choice for mass treatment is the microfilaricidal Mectizan(®) (ivermectin); it does not kill the adult stages of the parasite at the standard dose which is a single annual dose aimed at disease control. However, multiple treatments a year with ivermectin have effects on adult worms. The discovery of new therapeutic targets and drugs directed towards the killing of the adult parasites are thus urgently needed. The chitinase of filarial nematodes is a new drug target due to its essential function in the metabolism and molting of the parasite. Closantel is a potent and specific inhibitor of chitinase of Onchocerca volvulus (OvCHT1) and other filarial chitinases. However, the binding mode and specificity of closantel towards OvCHT1 remain unknown. In the absence of a crystallographic structure of OvCHT1, we developed a homology model of OvCHT1 using the currently available X-ray structures of human chitinases as templates. Energy minimization and molecular dynamics (MD) simulation of the model led to a high quality of 3D structure of OvCHIT1. A flexible docking study using closantel as the ligand on the binding site of OvCHIT1 and human chitinases was performed and demonstrated the differences in the closantel binding mode between OvCHIT1 and human chitinase. Furthermore, molecular dynamics simulations and free-energy calculation were employed to determine and compare the detailed binding mode of closantel with OvCHT1 and the structure of human chitinase. This comparative study allowed identification of structural features and properties responsible for differences in the computationally predicted closantel binding modes. The homology model and the closantel binding mode reported herein might help guide the rational development of novel drugs against the adult parasite of O. volvulus and such findings could be extrapolated to other filarial neglected diseases.
authors.affiliation: Laboratorio de Bioinformática, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro esquina Elías Piña, Colonia Narciso Mendoza, 88710, Ciudad Reynosa, Tamaulipas, México. asegurac@ipn.mx
authors.forename: Aldo
authors.initials: A
authors.lastname: Segura-Cabrera
authors.forename: Virgilio
authors.initials: V
authors.lastname: Bocanegra-García
authors.forename: Cristian
authors.initials: C
authors.lastname: Lizarazo-Ortega
authors.forename: Xianwu
authors.initials: X
authors.lastname: Guo
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.forename: Mario A
authors.initials: MA
authors.lastname: Rodríguez-Pérez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017181:Onchocerca volvulus / Q000187:drug effects / Q000201:enzymology*; D009855:Onchocerciasis / Q000188:drug therapy; D011485:Protein Binding; D012458:Salicylanilides / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000871:Anthelmintics; D012458:Salicylanilides; D002688:Chitinases; C023342:closantel
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