da C Silva Danielle, Maltarollo Vinicius G, de Lima Emmanuela Ferreira, Weber Karen Cacilda, Honorio Kathia M
Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, Brazil.
J Mol Model. 2014 Jul;20(7):2231. doi: 10.1007/s00894-014-2231-7. Epub 2014 Jun 17.
AT1 receptor is an interesting biological target involved in several important diseases, such as blood hypertension and cardiovascular pathologies. In this study we investigated the main electrostatic and steric features of a series of AT1 antagonists related to hypertensive activity using structure and ligand-based strategies (docking and CoMFA). The generated 3D model had good internal and external consistency and was used to predict the potency of an external test set. The predicted values of pIC50 are in good agreement with the experimental results of biological activity, indicating that the 3D model can be used to predict the biological property of untested compounds. The electrostatic and steric CoMFA maps showed molecular recognition patterns, which were analyzed with structure-based molecular modeling studies (docking). The most and the least potent compounds docked into the AT1 binding site were subjected to molecular dynamics simulations with the aim to verify the stability and the flexibility of the ligand-receptor interactions. These results provided valuable insights on the electronic/structural requirements to design novel AT1 antagonists.
AT1受体是一个涉及多种重要疾病的有趣生物学靶点，如高血压和心血管疾病。在本研究中，我们使用基于结构和配体的策略（对接和比较分子场分析法）研究了一系列与高血压活性相关的AT1拮抗剂的主要静电和空间特征。生成的三维模型具有良好的内部和外部一致性，并用于预测外部测试集的效力。pIC50的预测值与生物活性的实验结果高度一致，表明该三维模型可用于预测未测试化合物的生物学性质。静电和空间比较分子场分析法图谱显示了分子识别模式，并通过基于结构的分子建模研究（对接）进行了分析。对接至AT1结合位点的活性最强和最弱的化合物进行了分子动力学模拟，以验证配体-受体相互作用的稳定性和灵活性。这些结果为设计新型AT1拮抗剂的电子/结构要求提供了有价值的见解。
