title: Discovery of Entamoeba histolytica hexokinase 1 inhibitors through homology modeling and virtual screening.
abstract: Entamoeba histolytica, the parasite which causes amebiasis is responsible for 110,000 deaths a year. Entamoeba histolytica depends on glycolysis to obtain ATP for cellular work. According to metabolic flux studies, hexokinase exerts the highest flux control of this metabolic pathway; therefore, it is an excellent target in the search of new antiamebic drugs. To this end, a tridimensional model of E. histolytica hexokinase 1 (EhHK1) was constructed and validated by homology modeling. After virtual screening of 14,400 small molecules, the 100 with the best docking scores were selected, purchased and assessed in their inhibitory capacity. The results showed that three molecules (compounds 2921, 11275 and 2755) inhibited EhHK1 with an I50 of 48, 91 and 96 µM, respectively. Thus, we found the first inhibitors of EhHK1 that can be used in the search of new chemotherapeutic agents against amebiasis.
authors.affiliation: Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Veterinaria S/N Circuito Universitario , Durango , México .
authors.forename: María Leticia
authors.initials: ML
authors.lastname: Saucedo-Mendiola
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Salas-Pacheco
authors.forename: Hugo
authors.initials: H
authors.lastname: Nájera
authors.forename: Arturo
authors.initials: A
authors.lastname: Rojo-Domínguez
authors.forename: Lilián
authors.initials: L
authors.lastname: Yépez-Mulia
authors.forename: Claudia
authors.initials: C
authors.lastname: Avitia-Domínguez
authors.forename: Alfredo
authors.initials: A
authors.lastname: Téllez-Valencia
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry*; D055808:Drug Discovery; D004748:Entamoeba histolytica / Q000737:chemistry* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D006593:Hexokinase
keywords: Entamoeba histolytica; hexokinase 1; hit discovery; homology modeling; virtual screening