title: Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB.
abstract: Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases.
authors.affiliation: Molecular Discovery Sciences, MSD Animal Health Innovation GmbH, Schwabenheim, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schröder
authors.forename: Sandra
authors.initials: S
authors.lastname: Noack
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Marhöfer
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.forename: Paul M
authors.initials: PM
authors.lastname: Selzer
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D057056:Cysteine Proteases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012664:Semicarbazones / Q000737:chemistry* / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D011994:Recombinant Proteins; D012664:Semicarbazones; D013882:Thiosemicarbazones; D057056:Cysteine Proteases