by For has reduced mitochondrion lacking the components of oxidative phosphorylation, glucose degradation via glycolysis serves as a major source of ATP16. 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 KLHL22 antibody proposed region as a specific molecular binding site with pharmacological potential. infection is usually deceptive; the giardiasis contamination and treatment still symbolize important challenges nowadays. Punicalagin For example, recurrence rates are high in endemic areas and first-line therapy fails in up to 20% of cases6. In addition, important disadvantages are associated with the use of current therapies; especially the important side effects related to them6C8. Finally, clinical and laboratory-induced resistance to current drugs has been exhibited for this parasite9C12. The high prevalence and recurrence of giardiasis in disadvantaged populations, the undesirable Punicalagin side effects of their therapies and the presence of resistant strains indicates that the development of new antigiardiasis therapies is usually paramount. In this regard, multiple alternative methods aimed to develop optional therapies for giardiasis, including the use of natural products, vaccine generation, chemical synthesis of new drugs and rational drug design, are currently on progress1,5C7,9,10,13. Rational drug design makes use of the bioinformatical power currently available1. For infectious diseases, this approach attempts identifying a biomolecular target which is essential for the infectious agent; this target is usually then utilized for the search for compounds that impairs its function. Once a lead compound is recognized, it could be used as starting point in the lead optimization process1. For has reduced mitochondrion lacking the components of oxidative phosphorylation, glucose degradation via glycolysis serves as a major source of ATP16. Therefore, it has been proposed that disrupting the glycolytic pathway via inhibition of their enzymes could hinder the survival of the parasite14,15. The glycolytic enzyme fructose 1,6-bisphosphate aldolase (FBPA) from (GlFBPA) stands out as one of the most interesting molecular targets for rational drug design against giardiasis. It has been exhibited that inhibition of the GlFBPA gene transcription in trophozoites by interference RNA yielded no viable organisms15, thus validating GlFBPA as a potential drug target. In addition, the phylogenetic distribution of the enzyme supports the plausibility of GlFPBA as a selective target. The fructose 1,6-bisphosphate aldolase family encompass two individual classes of enzymes differing in their enzymatic mechanisms. The class I family employs an active site lysine in Schiff base formation whereas the class II aldolases employ a Zn2+ ion as cofactor. Human FBPA belongs to the class I family, whereas GlFBPA belongs to the class II aldolases17. Given that both families do not share any structural, functional or phylogenetic relationship18, Punicalagin it has been envisioned that designing drugs that selectively inhibits the parasitic enzyme without affecting the human enzyme is usually feasible15. In order to unravel the determinants of catalysis and substrate acknowledgement that could direct the discovering of specific enzyme inhibitors, the crystal structure of GlFBPA has been obtained in the ligand-free state and in complex with the substrate D-fructose Punicalagin 1,6-bisphosphate (F1,6P), the transition state analog phosphoglycolohydroxamate or the competitive inhibitor tagatose-1,6-bisphosphate15,19. The analysis from your GlFBPA crystal structures indicates a complex network of residues involved in substrate discrimination, including amino acids within the 1st, 2nd and higher level shells surrounding the ligand15,19. The structural features of the GlFBPA active site that govern ligand binding and the differences in the catalytic mechanisms of class I and class II aldolases have been exploited to design selective competitive inhibitors of the enzyme20. However, in the kinetic context of metabolic pathways, competitive inhibitors.
