In-silico analysis of bufadienolides as potential inhibitors of Trypanosoma nucleoside hydrolase

Abstract

Trypanosomiasis is one of the neglected tropical diseases which curtails the productivity of the victim and causes mortality in extreme cases. Non-availability of vaccines, low therapeutic index of trypanocidal drugs and development of resistance lead to the need for research focused on developing alternative treatment options against this disease. The aim of the current work is to use computer-assisted drug discovery techniques to examine the anti-trypanosomal action of bufadienolides, which are commonly detected in the skin secretions of toads. A library of 16 compounds from the bufadienolides family was tested for toxicity and docked against the Trypanosoma brucei hydrolase. The oral bioavailability and good suitability of the compounds for transdermal delivery was also indicated by the ADMET study. The findings based on molecular docking and dynamics simulation along with toxicity assessment showed that three compounds, marinobufagin, resibufogenin and resibufaginol, have the lowest toxicity and maximum binding energy against Trypanosoma brucei hydrolase. According to the results obtained by molecular docking interactions between drugs and target proteins are observed and contain a number of hydrogen bonds near the residues in the active pocket of the enzyme. The results of this study contribute to the understanding of the SAR of bufadienolides and provide a foundation for further research and drug development efforts. The computational analysis, including the density functional theory study, the knowledge of inhibitory mechanisms and aids in the design and optimization of novel anti-trypanosomal drugs.