Introduction: Angiotensin Converting Enzyme (ACE), a key enzyme in Renin Angiotensin System for production of angiotensin II and a mediator for hypertension, is a target for cardiovascular disease management. Arisawa et al. claim that the naturally occurring triterpene Rubiatriol, has ACE-inhibitory activity. This study aimed to, using Rubiatriol as lead molecule, validate this hypothesis using in silico techniques and to design novel high affinity structures for the ACE using de novo methods.

Methodology: Protein Databank crystallographic deposition 2C6N describing the ACE:Lisinopril complex, was selected as a template. Binding affinity of Lisinopril for the ACE was calculated using X-Score. Rubiatriol was docked into the ACE_Ligand Binding Pocket (LBP), and conformational analysis performed. Structure activity relationship data and 2D topology maps generated in Poseview highlighting the interactions of the optimal conformer with the LBP amino acids, guided the creation of five seed structures onto which novel growth was sustained within the ACE ligand binding pocket using the GROW module of LigBuilderv1.2. The generated molecular cohort was assessed for Lipinski Rule compliance.

Results:  The Lipinski rule compliant molecular cohort was, for each seed, segregated into families of similar pharmacophoric structure, and ranked according to binding affinity and physicochemical parameter. The highest ranking molecules were identified for optimisation and in vitro validation.

Discussion: This study is valuable for validation of the hypothesis of Arisawa et al. using in silico methods, and for suggesting that the rubiatriol scaffold was a suitable lead for the generation of ACE modulating molecules with a binding affinity superior to that of Lisinopril.