title: Design, synthesis, and evaluation of inhibitors of cathepsin L: Exploiting a unique thiocarbazate chemotype.
abstract: Recently, we identified a thiocarbazate that exhibits potent inhibitory activity against human cathepsin L. Since this structure represents a novel chemotype with potential for activity against the entire cysteine protease family, we designed, synthesized, and assayed a series of analogs to probe the mechanism of action, as well as the structural requirements for cathepsin L activity. Molecular docking studies using coordinates of a papain-inhibitor complex as a model for cathepsin L provided useful insights.
authors.affiliation: Penn Center for Molecular Discovery, University of Pennsylvania, 1024 Vagelos Research Laboratories, Philadelphia, PA 19104-6383, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Myers
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Beavers
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Napper
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
mesh_terms: D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D006834:Hydrazines; D013438:Sulfhydryl Compounds; C010877:carbazic acid; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; D010206:Papain