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.

中文翻译：

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发现与高血压相关的肾素-血管紧张素原复合物结合的新药物。

肾素（REN）是阻止高血压病发作的关键药物靶标，但到目前为止，只有一种直接抑制剂可以通过商业途径获得。在这项研究中，我们通过针对肾素：血管紧张素原（REN：ANG）复合物的界面来评估创新的REN抑制策略。我们表征了REN：ANG的界面残基的能量作用，并确定了负责蛋白质：蛋白质结合的残基，这些蛋白质可以用作破坏REN：ANG关联的药物靶标。为此，我们应用了计算性丙氨酸扫描诱变方案，该方案可测量每个侧链对蛋白质：蛋白质结合自由能的贡献，精确度约为1 kcal / mol。结果，在REN和ANG中，分别发现六个和八个残基对于结合至关重要。REN背后的主导力量：发现ANG络合是疏水作用。发现每个残基的结合自由能与掩埋面积成比例。负责结合的残基从复合物中的水中被封闭，这促进了两种蛋白质之间的有效配对。在REN的表面上发现了两个涉及结合关键残基的可药物化口袋，其中小的药物样分子可以结合并破坏ANG：REN结合，这可能提供实现REN抑制和控制高血压的有效途径。