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

LLANOS MANUEL; SBARAGLINI MARIA LAURA; VILLALBA MARIA LUISA; ALBA SOTO CATALINA; RUIZ DANIELA; CARRILLO CAROLINA; TALEVI ALAN; GAVERNET LUCIANA

Barcelona

Conferencia; International conference and exhibition of the Society for Laboratory Automation and Screening; 2019

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modeling, molecular dynamics and docking simulations allowed us to find high potency hits, with ki values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are strongly selective for TcCA over human carbonic anhydrase (CAII isoform), which is encouraging in terms of the therapeutic safety and efficacy.