Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi

Abstract

Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q 2 ¼ 0.75 and r 2 ¼ 0.96; classical QSAR, q 2 ¼ 0.72 and r 2 ¼ 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r

Structure-Based Drug Discovery for Tropical Diseases

“…Their implication in numerous vital processes of several parasitic protozoa makes them highly attractive targets for drug design [85,86]. Cruzain (EC 3.4.22), the major cysteine protease of T. cruzi, plays a pivotal role during the infection of host cells, replication, and metabolism, and has been extensively investigated as an attractive target for the development of a new generation of antitrypanosomal agents [87][88][89][90][91][92][93][94][95][96]. Indeed, cruzain inhibitors are amongst the most advanced compounds in the drug development pipeline for Chagas' disease.…”

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

“…Estratégias de VS por similaridade química ou modelos farmacofóricos permitem a investigação de conjuntos de dados com diversidade estrutural mais ampla do que aquela encontrada em estudos de QSAR. 37,42,44 Alguns exemplos ilustram a aplicação destas técnicas na identificação de novos esqueletos químicos (scaffold hopping). 40,45 Etapas de LBVS Em geral, os métodos de LBVS se fundamentam em estudos de similaridade ou em modelos construídos a partir de conjuntos de ligantes e não ligantes.…”

Structure- and ligand-based drug design approaches for neglected tropical diseases

“…Compound 5 was active only against closely related cysteine proteases, however, with significant SI values ranging from 80 (cathepsin-S) to 50.000 (cathepsin-B). The integration of SBDD and LBDD approaches has found its way into drug discovery programs for NTDs [32][33][34][35][36][37][38]. Good examples can be seen in the use of 3D QSAR methods, such as comparative molecular field analysis (CoMFA) [39,40] and comparative molecular similarity index analysis (CoMSIA) [41,42].…”