title: Exploring inhibitor binding at the S' subsites of cathepsin L.
abstract: We report a series of noncovalent, reversible inhibitors of cathepsin L that have been designed to explore additional binding interactions with the S' subsites. The design was based on our previously reported crystal structure that suggested the possibility of engineering increased interactions with the S' subsites ( Chowdhury et al. J. Med. Chem. 2002, 45, 5321-5329 ). A representative of these new inhibitors has been co-crystallized with mature cathepsin L, and the structure has been solved and refined at 2.2 A. The inhibitors described in this work extend farther into the S' subsites of cathepsins than any inhibitors reported in the literature thus far. These interactions appear to make use of a S3' subsite that can potentially be exploited for enhanced specificity and/or affinity.
authors.affiliation: Biotechnology Research Institute, National Research Council, Canada.
authors.forename: Shafinaz F
authors.initials: SF
authors.lastname: Chowdhury
authors.forename: Lissa
authors.initials: L
authors.lastname: Joseph
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: Shenoy Rajesh
authors.initials: SR
authors.lastname: Tulsidas
authors.forename: Sathesh
authors.initials: S
authors.lastname: Bhat
authors.forename: Edmund
authors.initials: E
authors.lastname: Ziomek
authors.forename: Robert
authors.initials: R
authors.lastname: Ménard
authors.forename: J
authors.initials: J
authors.lastname: Sivaraman
authors.forename: Enrico O
authors.initials: EO
authors.lastname: Purisima
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D055672:Static Electricity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; D014443:Tyrosine; D010649:Phenylalanine; D001120:Arginine; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L