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Structure-based identification of a potential non-catalytic binding site for rational drug design in the fructose 1,6-biphosphate aldolase from Giardia lamblia.
Méndez, Sara-Teresa; Castillo-Villanueva, Adriana; Martínez-Mayorga, Karina; Reyes-Vivas, Horacio; Oria-Hernández, Jesús.
Affiliation
  • Méndez ST; Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Alcaldía Coyoacán, CP 04530, Ciudad de México, Mexico.
  • Castillo-Villanueva A; Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Alcaldía Coyoacán, CP 04530, Ciudad de México, Mexico.
  • Martínez-Mayorga K; Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Alcaldía Coyoacán, C.P. 04510, Ciudad de México, Mexico.
  • Reyes-Vivas H; Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Alcaldía Coyoacán, CP 04530, Ciudad de México, Mexico. hreyesvivas@yahoo.com.mx.
  • Oria-Hernández J; Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Alcaldía Coyoacán, CP 04530, Ciudad de México, Mexico. jesus.oria.inp@gmail.com.
Sci Rep ; 9(1): 11779, 2019 08 13.
Article in En | MEDLINE | ID: mdl-31409864
ABSTRACT
Giardia lamblia is the causal agent of giardiasis, one of the most prevalent parasitosis in the world. Even though effective pharmacotherapies against this parasite are available, the disadvantages associated with its use call for the development of new antigiardial compounds. Based on the Giardia dependence on glycolysis as a main energy source, glycolytic enzymes appear to be attractive targets with antiparasitic potential. Among these, fructose 1,6-biphosphate aldolase (GlFBPA) has been highlighted as a promising target for drug design. Current efforts are based on the design of competitive inhibitors of GlFBPA; however, in the kinetic context of metabolic pathways, competitive inhibitors seem to have low potential as therapeutic agents. In this work, we performed an experimental and in silico structure-based approach to propose a non-catalytic binding site which could be used as a hot spot for antigardial drug design. The druggability of the selected binding site was experimentally tested; the alteration of the selected region by site directed mutagenesis disturbs the catalytic properties and the stability of the enzyme. A computational automated search of binding sites supported the potential of this region as functionally relevant. A preliminary docking study was performed, in order to explore the feasibility and type of molecules to be able to accommodate in the proposed binding region. Altogether, the results validate the proposed region as a specific molecular binding site with pharmacological potential.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Binding Sites / Giardiasis / Enzyme Inhibitors / Fructose-Bisphosphate Aldolase Type of study: Diagnostic_studies Limits: Animals / Humans Language: En Journal: Sci Rep Year: 2019 Type: Article Affiliation country: Mexico

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Binding Sites / Giardiasis / Enzyme Inhibitors / Fructose-Bisphosphate Aldolase Type of study: Diagnostic_studies Limits: Animals / Humans Language: En Journal: Sci Rep Year: 2019 Type: Article Affiliation country: Mexico