Fostering the hit identification process: structure-based virtual screening substantially increases hit-rate

LLANOS MANUEL; SBARAGLINI, MARÍA L.; VILLALBA MARIA L.; RUIZ, MARÍA D.; CARRILLO, CAROLINA; SOTO, CATALINA ALBA; TALEVI, ALAN; SUPURAN CLAUDIU .T; GAVERNET, L

BARCELONA

Conferencia; SLAS2019 International Conference & Exhibition; 2019

SLAS

T. cruzi Carbonic Anhydrase (TcCA) has recently emerged as a promising target to derive novel therapeutic opportunities against Chagas disease. Nevertheless, the lack of high-quality structural data has hindered the rational design of novel and selective inhibitors of this enzyme. To address this challenge, a docking model to predict TcCA inhibition was developed and properly validated. The model was applied in a virtual screening campaign and some interesting hits were selected for in-vitro evaluation on the enzyme inhibition assay. Additionally, we also tested the trypanocidal activity of the compounds in the epimastigote and trypomastigote forms of the parasite.Among the 10 evaluated compounds, 8 of them were nanomolar inhibitors of TcCA; which represents an 80 % hit rate. We found this model particularly useful to create target-focused compounds libraries, substantially increasing the potential hit rate, which translates into a significant saving of time and money.