Discovery of Trypanocidal Bioactive Leads by Docking Study, Molecular Dynamic Simulation and In Vivo Screening

Abstract

AbstractNine selected potential antitrypanosomal hits from plants obtained by docking calculation according to the docking protocols implemented in Molecular Operating Environment were further screened by evaluating their binding affinities toward an ‘all important’ antitrypanosomal drug target – trypanothione reductase (TryR), which is absent in humans, using a more stringent scoring function obtainable in AutoDock vina. All the compounds showed binding affinity for TryR at the range of −4.90±1.78 to −8.70±0.22 Kcal/mol. Also, the compounds demonstrated affinity toward an analogous enzyme to TryR, glutathione reductase (GR) that is found in vertebrates which suggests that they could pose a selectivity challenge. However, on comparison, β‐sitosterol; the candidate that scored topmost against three out of six earlier studied antitrypanosomal drug targets (uridylyl transferase ‐ UTF, farnesyl diphosphate synthase ‐ FDS and adenosine kinase ‐ ADK), showed a significant (P<0.05) binding affinity for TryR (‐8.70±0.22 Kcal/mol) over GR (‐7.50±0.36 Kcal/mol). The complexes formed between β‐sitosterol and the proteins: UTF, FDS and ADK, remained stable over 100 ps molecular dynamic simulation. Moreover, 200 mg/kg b.w. of the candidate significantly (P<0.05) killed the pathogen in T. b. brucei infected mice from third day post treatment. This study presents β‐sitosterol as an interesting antitrypanosomal candidate.