Abstract
A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.
MeSH terms
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Amino Acid Substitution
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Binding Sites
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Cathepsins / antagonists & inhibitors*
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Cathepsins / genetics
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Cathepsins / metabolism
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Crystallography, X-Ray
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Drug Design
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Humans
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Mutagenesis, Site-Directed
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Protease Inhibitors
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Pyrazoles
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Pyridines
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Recombinant Proteins
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Cathepsins
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cathepsin S