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.
Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors
