肺动脉高压（PAH）是一类恶性肺血管疾病，新靶点药物开发是其重点研究方向。磷酸二酯酶二型PDE2作为PAH潜在靶点，其抑制剂骨架多样性不足且分子识别机制不明，限制了PDE2抑制剂抗PAH药物的开发。申请人首次运用基于分子动力学的虚拟筛选方法高效发现5类全新骨架PDE2抑制剂，其中萘内酰亚胺类化合物经改造获得苗头物1708（570nM）。项目组近期获得1708与PDE2共晶结构，发现其与残基Q812存在氢键作用（未见文献报道）。在此基础上，拟采用项目组自主研发的自由能微扰新方法GA-FEP，定向蛋白关键残基（Q812和Q859）及疏水口袋，开展结构筛选和优化，以获得1-3个高PDE2活性、高亚型选择性、成药性好和体内PAH药效显著的先导物；利用结构生物学定点突变等技术阐明抑制剂与蛋白选择性识别机制。本项目将为新骨架PDE2抑制剂的理性设计及其作为PAH新靶点药物的开发提供理论和科学依据。

Pulmonary arterial hypertension (PAH) is a type of malignant pulmonary vascular disease, and development of new-targeted drugs is in great demand in research. Phosphodiesterase 2 (PDE2) is a potential target of PAH, however, PDE2 inhibitors exhibit less skeleton diversity and ambiguous molecular recognition, limiting their clinical application in PAH. Five types of PDE2 inhibitors with novel scaffolds were discovered by molecular dynamics-based virtual screening for the first time. Hit 1708 derived from benzo[cd]indol-2(1H)-ones exhibited inhibitory activity against PDE2 with IC50 of 570 nM. The co-crystal structure newly resoluted by us revealed an unreported hydrogen bond between 1708 and Q812 of PDE2. Based on these evidences, we intended to perform screening and structural optimization on 1708 by focusing on key residues (Q812 and Q859) and a unique hydrophobic pocket in PDE2 catalytic domain with GA-FEP method newly developed by our group. One to three drug-like leads will be obtained with good inhibitory activity/selectivity, drug-like property and in vivo efficacy. Further study on mechanism of the selective recognition between leads and PDE2 will be performed with site-directed mutagenesis and structural biology techniques. This project will provide theoretical and scientific basis for rational design of novel-scaffolded PDE2 inhibitors and development of new-targeted drugs for PAH.