Discovery of Renin Inhibitors through the Approach of Molecular Docking and Fragment-Based Drug Design

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.