Structure-Based Design and In Silico Evaluation of a Lipophilic Cyclooctanoyl-Derivative as a Renin Inhibitor: Lessons from Withdrawn Aliskiren

Renin, a key aspartic protease central to the renin–angiotensin–aldosterone system (RAAS), remains a therapeutic target for hypertension despite the withdrawal of the only approved direct renin inhibitor, Aliskiren, due to unfavorable drug–drug interactions and safety concerns. Here, we report a computational protein design-driven evaluation of (S)-3-((3-(1H-imidazol-1-yl)propyl)amino)-2-(((S)-1-carboxy-2-(cyclooctanecarboxamido)ethyl)amino)-3-oxopropanoic acid (N-CDAH), a novel lipophilic cyclooctanoyl- derivative , as a next-generation renin inhibitor scaffold. This scaffold was designed based on the rationale of leveraging the carnosine like backbone while optimizing lipophilicity and metabolic stability. Pharmacokinetic, ADME, and toxicity predictions (SwissADME, pkCSM) revealed greater predicted aqueous solubility, enhanced metabolic stability, and significantly reduced off-target liabilities compared with Aliskiren (specifically, non-inhibition of major CYP isoforms). Molecular docking (AutoDock Vina binding affinity: −8.08 kcal/mol; Maestro Induced Fit Docking score: −11.149 kcal/mol) and molecular dynamics simulations confirmed favorable binding interactions, conformational adaptability, and complex stability within the renin active site. To contextualize its performance within the broader chemical space, the diastereomeric analog of N-CDAH as well as structurally related compounds identified through SwissSimilarity were also examined using computational workflow. The MD analysis (200 ns) demonstrated that the inhibitor is anchored via a dual stabilization mechanism: hydrophobic enclosure coupled with persistent ionic interactions. These integrative in silico results highlight the potential of this derivative to overcome Aliskiren’s pharmacological shortcomings, providing a strong computational rationale for experimental validation and underscoring the role of structure-based drug design in antihypertensive drug discovery.