Lupeol acetate and alpha-amyrin terpenes activity against 'Trypanosoma cruzi': Insights into toxicity and potential mechanisms of action

• Published in: Tropical medicine and infectious disease Vol. 8; no. 5; pp. 1 - 18
• Main Authors: Pardo-Rodriguez, Daniel, Cifuentes-López, Andres, Bravo-Espejo, Juan, Romero, Ibeth, Robles, Jorge, Cuervo, Claudia, Mejía, Sol M., Tellez, Jair
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland MDPI 03.05.2023; MDPI AG
• Subjects: Algorithms; Analysis; Chagas disease; cysteine synthase; docking; Drugs; Enzymes; Immunological aspects; Ligands; molecular dynamics; Oxidative stress; Parasitic diseases; Prevention; Proteins; Protozoa; Simulation; Terpenes; terpenes trypanocidal effect; Tropical diseases; Trypanosoma cruzi; Argentina; Chagas disease; docking; cysteine synthase; molecular dynamics; terpenes trypanocidal effect; Trypanosoma cruzi
• ISSN: 2414-6366; 2414-6366
• DOI: 10.3390/tropicalmed8050263

Background: Chagas disease is a potentially fatal disease caused by the parasite 'Trypanosoma cruzi'. There is growing scientific interest in finding new and better therapeutic alternatives for this disease's treatment. Methods: A total of 81 terpene compounds with potential trypanocidal activity were screened and found to have potential 'T. cruzi' cysteine synthase (TcCS) inhibition using molecular docking, molecular dynamics, ADME and PAIN property analyses and in vitro susceptibility assays. Results: Molecular docking analyses revealed energy ranges from −10.5 to −4.9 kcal/mol in the 81 tested compounds, where pentacyclic triterpenes were the best. Six compounds were selected to assess the stability of the TcCS-ligand complexes, of which lupeol acetate (ACLUPE) and alpha-amyrin (AMIR) exhibited the highest stability during 200 ns of molecular dynamics analysis. Such stability was primarily due to their hydrophobic interactions with the amino acids located in the enzyme's active site. In addition, ACLUPE and AMIR exhibited lipophilic characteristics, low intestinal absorption and no structural interferences or toxicity. Finally, selective index for ACLUPE was >5.94, with moderate potency in the trypomastigote stage (EC50 = 15.82 +- 3.7 mug/mL). AMIR's selective index was >9.36 and it was moderately potent in the amastigote stage (IC50 = 9.08 +- 23.85 mug/mL). Conclusions: The present study proposes a rational approach for exploring lupeol acetate and alpha-amyrin terpene compounds to design new drugs candidates for Chagas disease.