Discovery of new sites for drug binding to the hypertension-related renin-angiotensinogen complex.
Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.
Natércia F
NF
Brás
Pedro A
PA
Fernandes
Maria J
MJ
Ramos
D000808:Angiotensinogen / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D055808:Drug Discovery; D057927:Hydrophobic and Hydrophilic Interactions; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D012083:Renin / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D000808:Angiotensinogen; D012083:Renin