Identification of a novel potassium channel (GiK) as a potential drug target in Giardia lamblia: Computational descriptions of binding sites

PeerJ. 2019 Feb 27;7:e6430. doi: 10.7717/peerj.6430. eCollection 2019.

Abstract

Background: The protozoan Giardia lamblia is the causal agent of giardiasis, one of the main diarrheal infections worldwide. Drug resistance to common antigiardial agents and incidence of treatment failures have increased in recent years. Therefore, the search for new molecular targets for drugs against Giardia infection is essential. In protozoa, ionic channels have roles in their life cycle, growth, and stress response. Thus, they are promising targets for drug design. The strategy of ligand-protein docking has demonstrated a great potential in the discovery of new targets and structure-based drug design studies.

Methods: In this work, we identify and characterize a new potassium channel, GiK, in the genome of Giardia lamblia. Characterization was performed in silico. Because its crystallographic structure remains unresolved, homology modeling was used to construct the three-dimensional model for the pore domain of GiK. The docking virtual screening approach was employed to determine whether GiK is a good target for potassium channel blockers.

Results: The GiK sequence showed 24-50% identity and 50-90% positivity with 21 different types of potassium channels. The quality assessment and validation parameters indicated the reliability of the modeled structure of GiK. We identified 110 potassium channel blockers exhibiting high affinity toward GiK. A total of 39 of these drugs bind in three specific regions.

Discussion: The GiK pore signature sequence is related to the small conductance calcium-activated potassium channels (SKCa). The predicted binding of 110 potassium blockers to GiK makes this protein an attractive target for biological testing to evaluate its role in the life cycle of Giardia lamblia and potential candidate for the design of novel antigiardial drugs.

Keywords: Docking; Giardia lamblia; Molecular modeling; Potassium channel; Potential target.

Grant support

Lissethe Palomo, Filiberto Gutiérrez and Verónica Ochoa awarded scholarships 377019, 574252 and 575532 from CONACYT. This work was partially supported by the Fondo Sectorial de Investigación en Salud y Seguridad Social (CONACYT-FOSISS 2015-1-261442). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.