Identification of inhibitors as drug candidates against Chagas disease

Author(s)

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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 248, p. 17-pg., 2023-01-07.

Abstract

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)

• FAPESP's process: 21/02789-7 - Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 16/24524-7 - STRUCTURAL ANALYSIS AND MOLECULAR MODELING STUDIES FOR NATURAL AND SYNTHETIC LIGANTS RELATED TO NEGLECTED DISEASES
• Grantee: Kathia Maria Honorio
• Support Opportunities: Regular Research Grants