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1.
Bioorg Med Chem ; 13(6): 2141-56, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15727867

ABSTRACT

Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T. cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3A crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization.


Subject(s)
Chagas Disease/drug therapy , Chagas Disease/parasitology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Protozoan Proteins/antagonists & inhibitors , Trypanosoma cruzi/enzymology , Amides/chemistry , Animals , Cell Line , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/therapeutic use , Esters/chemistry , Inhibitory Concentration 50 , Kinetics , Mice , Models, Molecular , Molecular Structure , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism
2.
J Chem Inf Model ; 45(1): 2-9, 2005.
Article in English | MEDLINE | ID: mdl-15667123

ABSTRACT

This paper describes ArQiologist, a Web-based tool that integrates chemical, analytical, biological, and computational data to facilitate decision support for lead optimization at ArQule. It features an easy-to-use graphical query builder that allows queries to be saved, reused, and shared by researchers. Query results can be viewed with built-in data browsers or exported with structures to external applications such as Microsoft Excel or Spotfire for further analysis.

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