Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

ABSTRACT: A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive pro

SUBMITTER: Wiggers HJ 

PROVIDER: S-EPMC3750009 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature