In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ÎCTE, fused benzo[b]thiophenes and Î²,Î²Ê¹-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%â90% inhibition of the target enzyme at 20Â Î¼m). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3Ê¹-triketones with a Y-topology. Based on the predicted physicochemical and ADMEâTox properties, compound 2b has been identified as a new drug-like, non-mutagen, non-carcinogen, and non-neurotoxic lead candidate.
|Titolo:||Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE|
RESCIFINA, Antonio (Corresponding)
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||1.1 Articolo in rivista|