Investigation of Drug Interaction Potentials and Binding Modes on Direct Renin Inhibitors: A Computational Modeling Studies

Background: Hypertension is one of the key risk factors for cardiovascular disease, it is regulated through Renin Angiotensin Aldosterone System (RAAS) cascade. Renin catalyzes the initial rate-limiting step in RAAS system, that influences the synthesis of angiotensin I from precursor angiotensin. Renin inhibition could be a potential step for the blood pressure lowering mechanism as well as for organ protection. Methods: In order to understand the structure-activity association of direct renin inhibitors (DRIs), we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking studies and Density Functional Theory (DFT) analysis to identify the attractive compounds. Five-point pharmacophore model of one acceptor, three hydrophobic groups and one aromatic ring was chosen for the dataset of 40 compounds. Results: The generated 3D-QSAR model shows that the alignment has a good correlation coefficient for the training set compounds, which comprise the value of R2 = 0.96, SD = 0.1, and F = 131.3. The test compounds had Q2 = 0.91, RMSE = 0.25, and Pearson-R = 0.97, which describes the predicted model was reliable. Discussion: External validations were carried out to validate the predicted QSAR model. Further, the significant compounds were studied using different in silico approaches in order to explore the difference in the atomic configuration and binding mechanism of the identified compounds. Conclusion: The molecular dynamics simulation of the complex was analyzed and confirmed the stability of the compounds in the protein. The outcome of the result could be useful to improve the safety and efficacy of DRIs that can be projected to clinical trials.