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Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE
Author(s) -
Scala Angela,
Rescifina Antonio,
Micale Nicola,
Piperno Anna,
Schirmeister Tanja,
Maes Louis,
Grassi Giovanni
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13124
Subject(s) - cysteine , chemistry , adme , cysteine protease , virtual screening , drug discovery , covalent bond , biochemistry , cysteine proteinase inhibitors , enzyme , docking (animal) , in vitro , stereochemistry , combinatorial chemistry , programmed cell death , caspase , organic chemistry , apoptosis , medicine , nursing
In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[ b ]thiophenes and β,β ʹ ‐triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate‐to‐excellent activity (12%–90% inhibition of the target enzyme at 20 μ m ). 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 1,3,3ʹ‐triketones with a Y‐topology. Based on the predicted physicochemical and ADME–Tox properties, compound 2b has been identified as a new drug‐like, non‐mutagen, non‐carcinogen, and non‐neurotoxic lead candidate.