In-silico and in-vivo evaluation of the Cardiovascular effects of five Leonotis leonurus diterpenes

Abstract

BackgroundLeonotis leonurus extracts and compounds have been extensively studied for pharmacological effects. However, most of the diterpenes isolated from the plant have not been evaluated as possible contributors to the cardiovascular effects of the plant extracts. In this study, computational modelling was used to predict the drug-likeness and cardiovascular effects of five diterpenoids of L. Leonurus. The predicted results were then subsequently compared with results obtained from anaesthetized normotensive Wistar rats to determine the most likely lead compounds for drug development. MethodsMolecular operating environment (MOE) software was used to assess the drug-likeness and molecular docking interactions between the diterpenoids and the angiotensin-converting enzyme (ACE) (PDB; 2 × 8Z), the angiotensin receptor (AT1) (PDB; 3R8A) and the β1 receptor (PDB; 2Y04). The predicted cardiovascular effects were assessed in the anaesthetized normotensive Wistar rat model. ResultsDubiin and saponified dubiin were the most drug-like, while DC9 was the least drug-like diterpene. The interactions between the ACE and marrubiin and saponified dubiin were similar to ACE and captopril but lacked interactions with the zinc ion. None of the compounds interacted with the angiotensin receptor similar to HIG (native ligand), suggesting there was no AT1 blockade. Binding with the β1 receptor was similar to that of salbutamol, suggesting a β1 agonist activity. In the in vivo study, statistically significant (p < 0.05) increases in SP, and MAP were observed with hispanol and DC9, while a significant (p < 0.05) increase in HR occurred with the administration of hispanol only. ConclusionAs predicted from the in silico studies, none of the five diterpenes acted as inhibitors of ACE or AT1. Hispanol produced cardiovascular effects suggestive of β1 agonism in vivo. The in silico predictions correlated well with in vivo observations and allowed for improved determination of the ideal lead compound for drug development.