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.
Highlights
Infectious diseases caused or transmitted by parasites are worldwide public-health issues, in underdeveloped countries[1]
In the search for a druggable target binding site in GlFBPA, three main characteristics were pursued: (i) The selected region should be important for the structure or the function of the protein, such that its modification exert a negative effect on the enzyme. (ii) The selected region should be different to the active site, to avoid developing a molecule acting as a competitive inhibitor. (iii) The selected region should be accessible to external molecules, such that a small molecule can bind on it
The selected region must be important for the structure or the function of the protein: We hypothesized that protein residues that are conserved through evolution must play a main role on the structure or function of GlFBPA, such that modification of these residues is precluded
Summary
Infectious diseases caused or transmitted by parasites are worldwide public-health issues, in underdeveloped countries[1]. Www.nature.com/scientificreports giardiasis in disadvantaged populations, the undesirable side effects of their therapies and the presence of resistant strains indicates that the development of new antigiardiasis therapies is paramount In this regard, multiple alternative approaches 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 progress[1,5,6,7,9,10,13]. The glycolytic enzyme fructose 1,6-bisphosphate aldolase (FBPA) from Giardia lamblia (GlFBPA) stands out as one of the most interesting molecular targets for rational drug design against giardiasis. The analysis from the 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 ligand[15,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
