PDE4/PDE7双重抑制剂的合理化设计

Phosphodiester 4 and 7 (PDE4 and PDE7) are important targets for anti-inflammation drugs.PDE4/PDE7 dual-specific inhibitors suppress the side effect (such as nausea and vomit) brought by the PDE4-specific inhibitors and thus are hopeful to be the next generation of anti-inflammation drugs. In previous NSFC subject, we had studied the detailed reaction pathway and Gibbs free energy barrier of PDE4-catalyzed hydrolysis of its substrate. Based on the studies on PDE4, in this project we will continue to employ multiple state-of-the-art computational techniques to investigate the foundmental reaction pathway of the PDE7-catalyzed hydrolysis of its substrate and the corresponding Gibbs free energy barrier, and to study the interactions of PDE4 and PDE7 with the PDE4/PDE7 dual-specific inhibitors. Based on these studies, we will design and predict novel potent PDE4/PDE7 dual-specific inhibitor structures followed by organic synthesis studies and biological activities tests. Based on the wet experimental results obtained, we will carry out inhibitor structure redesign followed by synthesis and biological activity study. These studies will provide a reasonable structure-activity relationship of PDE4/PDE7 dual-specific inhibitors. The ligand structures obtained will be hopeful to be the candidate drugs for the treatment of inflammation-related disease such as chronic obstructive pulmonary disease (COPD),asthma and inflammation.

磷酸二酯酶4和7（PDE4和PDE7）是抗炎药物分子的重要作用靶标。PDE4/PDE7双重抑制剂能够避免PDE4抑制剂药物所带来的副作用（如恶心和呕吐等），有希望成为新一代的抗炎药物。上一个基金项目中，我们研究了PDE4酶催化水解底物的反应途径及活化自由能。本项目将在此基础上，利用多种现代化学计算手段继续研究PDE7酶催化水解底物的详细反应途径及活化自由能，研究PDE4、PDE7酶与PDE4/PDE7双重抑制剂的作用规律。在此基础上，我们将设计和预测一系列结构新颖的可能具有更高活性和选择性的PDE4/PDE7双重抑制剂，并进行有机合成和生物活性测试研究。然后根据反馈的实验数据进行再设计，合成以及生物活性测试，以建立合理的分子结构-抑制活性构效关系。我们设计的抑制剂分子将有希望成为治疗与炎症相关的疾病如COPD，哮喘和炎症的候选药物。

磷酸二酯酶4和7（PDE4和PDE7）是抗炎药物分子的重要作用靶标。PDE4/PDE7双重抑制剂能够避免PDE4抑制剂药物所带来的副作用（如恶心和呕吐等），有希望成为新一代的抗炎药物。项目中我们利用多种现代化学计算手段研究了这两种酶催化水解底物的详细反应途径及活化自由能，研究了PDE4、PDE7酶与PDE4/PDE7双重抑制剂的作用规律。在这些研究的基础上，我们发展了一套合理的PDE4/PDE7双重抑制剂结合自由能预测方法，建立了可靠的双重抑制剂三维药效团模型用于虚拟筛选，并通过模拟和实验方法获得了7个结构新颖的高抑制活性的PDE4/PDE7双重抑制剂结构，用于以后的分子生物学研究和动物模型试验。这些抑制剂分子将有希望成为治疗与炎症相关的疾病如COPD，哮喘和炎症的候选药物。