Discovery of Entamoeba histolytica hexokinase 1 inhibitors through homology modeling and virtual screening. (June 2014)

• Record Type: Journal Article
• Authors: Saucedo-Mendiola, María Leticia; Salas-Pacheco, José Manuel; Nájera, Hugo; Rojo-Domínguez, Arturo; Yépez-Mulia, Lilián; Avitia-Domínguez, Claudia; Téllez-Valencia, Alfredo
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 29:Number 3(2014:Jun.)
• Page Start: 325
• Page End: 332
• Publication Date: 2014-06
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2013.779265
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title>Abstract</title> <p> <italic>Entamoeba histolytica</italic>, the parasite which causes amebiasis is responsible for 110 000 deaths a year. <italic>Entamoeba histolytica</italic> 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 <italic>E. histolytica</italic> 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 <bold>2921</bold>, <bold>11275</bold> and <bold>2755</bold>) 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.</p> </abstract>