title: Acridone alkaloids as potent inhibitors of cathepsin V.
abstract: Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 μM). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i)=1.2 μM; 6, K(i)=1.0 μM; 7, K(i)=0.2 μM; and 11, K(i)=1.7 μM). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM.
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
authors.forename: Richele P
authors.initials: RP
authors.lastname: Severino
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.forename: Emerson F
authors.initials: EF
authors.lastname: Marques
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
authors.forename: M Fátima das G F
authors.initials: MF
authors.lastname: da Silva
authors.forename: João B
authors.initials: JB
authors.lastname: Fernandes
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Vieira
mesh_terms: D000166:Acridines / Q000737:chemistry*; D054831:Acridones; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D054831:Acridones; D000470:Alkaloids; D015853:Cysteine Proteinase Inhibitors; C041300:acridone; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C117627:CTSV protein, human