Molecular Modelling Study of Heteroarylamide/Sulfonamide Compounds with Antitrypanosomal Activity

• Published in: Journal of the Brazilian Chemical Society Vol. 32; no. 1; pp. 83 - 97
• Main Authors: Souza, André, Cardoso, Fábio, Martins, Lucas, Alves, Cláudio, Silva, José, Molfetta, Fábio
• Format: Journal Article
• Language: English; Portuguese
• Published: Sociedade Brasileira de Química 2021
• Subjects: CHEMISTRY, MULTIDISCIPLINARY; Chagas disease; cruzain; molecular docking; molecular dynamics; QSAR; PLS
• ISSN: 0103-5053; 1678-4790
• DOI: 10.21577/0103-5053.20200158

According to the World Health Organization (WHO), Chagas disease (CD), whose etiological agent is the Trypanosoma cruzi (T. cruzi) parasite, affects about eight million people, mainly in Latin America. The cruzain enzyme is highlighted among the main biological targets, since it is the most abundant of the cysteine protease class from T. cruzi and is involved in the entire life cycle of the parasite, essential in regulating the interaction between parasite and host. The drugs available for the treatment of CD usually have strong side effects, and the nitro(triazole/imidazole)-based heteroarylamide/sulfonamide compounds (HA/S) emerge with high antitrypanosomal potential. In this study, the quantitative structure-activity relationship (QSAR) were built using partial least squares (PLS) regression, and the results were robust and adequate for predicting and proposing five new derivatives according to the statistical parameters. The docking results suggest that the best-scored HA/S derivatives showed hydrogen bonds with the residuals that comprise the catalytic region of the enzyme. The molecular dynamics (MD) simulations, performed with different methods, revealed the strong stability of the compound obtained by the QSAR model of this study, in addition to a better binding free energy value than the HA/S obtained from literature.