Abstract:
Direct renin inhibitors are third-generation non-peptide antihypertensive medications that directly inhibit the renin enzyme. Renin is a rate-limiting enzyme of
the Renin- Renin-Angiotensin-Aldosterone-System (RAAS). The over-expression
of renin leads to a dysregulated RAAS pathway. This causes the development of
diseases like hypertension, cardiovascular disease, and renal dysfunction. The early
intervention of the pathway, by the direct renin inhibitors, can prevent disease progression. Until now, Aliskiren is the only FDA-approved direct renin inhibitor that
has its limitations and its usage as an antihypertensive agent is still under question.
This research study aims to discover and design novel compounds, that can act
as potential direct renin inhibitors. Through the hybrid approach of structure-based
and ligand-based virtual screening, 2376 active CHEMBL and 56 ZINC compounds
were identified. The binding affinity of these compounds was assessed through the
molecular docking approach which was performed at the two known binding sites of
renin. The binding affinity score of Aliskiren, -10 kJ/mol, was taken as a reference.
For the first binding site, located at Chain C, 65 active CHEMBL and 2 ZINC compounds performed well. For the second binding site, located at Chain O, 106 active
CHEMBL compounds and two ZINC compounds, exhibited a good binding score. A
total of 20 active CHEMBL compounds performed well on both binding sites. Additionally, through ADME analysis, the pharmacokinetic profile of these compounds
was evaluated. Lastly, thirteen novel non-peptide direct renin inhibitors were designed,
through fragment-based drug design. Based on the molecular weight and the ADME
profile, 11 best-docked ZINC compounds were selected for this purpose. These novel
inhibitors exhibited an improved interaction profile and a docking score, in comparison to the FDA-approved drug. Thus, this study provides a comprehensive workflow
for the virtual screening and designing of compounds that can act potentially as renin
inhibitors.
