Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

6533b82bfe1ef96bd128e0f0

RESEARCH PRODUCT

Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

Tanja Schirmeister Angela Scala Giovanni Grassi Antonio Rescifina Anna Piperno Nicola Micale Louis Maes

subject

Cell Survival Leishmania mexicana Protozoan Proteins ADME-Tox; Benzo[b]thiophenes; Cysteine protease; Leishmaniasis; Triketones Thiophenes Cysteine Proteinase Inhibitors 010402 general chemistry 01 natural sciences Biochemistry Leishmania mexicana Cysteine Proteinase Inhibitors Cell Line Inhibitory Concentration 50 Structure-Activity Relationship Cysteine Proteases Catalytic Domain Drug Discovery Humans Structure–activity relationship cysteine protease Binding site ADME-Tox; benzo[b]thiophenes; cysteine protease; leishmaniasis; triketones; Biochemistry; Molecular Medicine Biology leishmaniasis Pharmacology chemistry.chemical_classification Virtual screening Binding Sites biology 010405 organic chemistry Pharmacology. Therapy Organic Chemistry triketones biology.organism_classification Cysteine protease 0104 chemical sciences Molecular Docking Simulation Chemistry Enzyme Biochemistry chemistry Docking (molecular)ADME-Tox Molecular Medicine benzo[b]thiophenes

description

Abstract: In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8CTE, fused benzo[b]thiophenes and ,'-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 20m). 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 1,3,3'-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.

year	journal	country	edition	language
2018-01-01

10.1111/cbdd.13124 http://hdl.handle.net/20.500.11769/323068