Identification of inhibitors as drug candidates against Chagas disease

Autor(es)

Araujo, Sheila Cruz ; de Angelo, Rafaela Molina ; Barbosa, Henrique ; Costa-Silva, Thais Alves ; Tempone, Andre Gustavo ; Lago, Joao Henrique Ghilardi ; Honorio, Kathia Maria

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 248, p. 17-pg., 2023-01-07.

Resumo

Chagas disease, after more than a century after its discovery, is still a major public health problem. It is estimated that approximately 10 million people worldwide are infected with T. cruzi. However, the situation is more critical in Latin America and other regions where the disease is endemic. The largest number of cases occurs in Brazil, Argentina, and Mexico as more than 100 million people in these regions are located in areas with a high risk of contamination by the vector. The need for new therapeutic alternatives is urgent, as the available drugs have severe limitations such as low efficacy and high toxicity. From this scenario, in this work, we employed the virtual screening technique using cruzain and BDF2 as key biological targets for the survival of the parasite. Our objective was to identify potential inhibitors of T. cruzi trypomastigotes, which could be considered drug can-didates against Chagas disease. For this, we employed different in silico methodologies and the obtained results were corroborated using in vitro biological assays. For the VS studies, a database containing synthetic compounds was simulated at the binding site of cruzain and BDF2. In addition, pharmacophoric models were constructed in the initial phases of VS, as well as other advanced analyses (molecular dynamics simulations, calculations of binding free energy, and ADME prediction) were carried out and the results allowed the selection of potential inhibitors of T. cruzi. Based on the obtained data, 32 different compounds commercially available were subjected to biological tests against the trypomastigote form of T. cruzi. As result, 11 of those compounds displayed sig-nificant activity against T. cruzi and can be considered potential candidates for the treatment of Chagas disease. (AU)

• Processo FAPESP: 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 16/24524-7 - Análise estrutural e estudos de modelagem molecular para ligantes de origem natural e sintética relacionados a doenças negligenciadas
• Beneficiário: Kathia Maria Honorio
• Modalidade de apoio: Auxílio à Pesquisa - Regular