Acridone alkaloids as potent inhibitors of cathepsin V
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
20/10/2012
20/10/2012
2011
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Resumo |
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 mu M). 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 mu M; 6, K(i) = 1.0 mu M; 7, K(i) = 0.2 mu M; and 11, K(i) = 1.7 mu M). 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. (C) 2011 Elsevier Ltd. All rights reserved. State of Sao Paulo Research Foundation (FAPESP, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) National Council for Scientific and Technological Development (CNPq, Conselho Nacional de Pesquisa e Desenvolvimento), Brazil |
Identificador |
BIOORGANIC & MEDICINAL CHEMISTRY, v.19, n.4, p.1477-1481, 2011 0968-0896 http://producao.usp.br/handle/BDPI/30079 10.1016/j.bmc.2010.12.056 |
Idioma(s) |
eng |
Publicador |
PERGAMON-ELSEVIER SCIENCE LTD |
Relação |
Bioorganic & Medicinal Chemistry |
Direitos |
restrictedAccess Copyright PERGAMON-ELSEVIER SCIENCE LTD |
Palavras-Chave | #Cathepsin V #Enzyme inhibitors #Natural products #Acridone alkaloids #LYSOSOMAL CYSTEINE PROTEASES #GLUTINOSA BL. MERR #CANCER-CELL LINES #SWINGLEA-GLUTINOSA #DRUG TARGETS #DESIGN #PROTEINASE #Biochemistry & Molecular Biology #Chemistry, Medicinal #Chemistry, Organic |
Tipo |
article original article publishedVersion |