Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC₅₀ = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC₅₀ = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5′-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.

磷酸二酯酶2（PDE2）已被广泛用于中枢神经系统（CNS）疾病和肺动脉高压的潜在治疗。在本文中，我们 通过基于结构的虚拟筛选和生物测定法确定了FDA批准的药物clofarabine （4）具有潜在的PDE2抑制活性（IC ₅₀ = 3.12± 0.67μM ）。考虑PDE2，一系列基于结构和结合模式嘌呤核苷衍生物的潜在治疗益处4设计，合成并评价，这导致最佳的化合物的发现14E与抑制效力的显著改善（IC ₅₀ = 0.32±0.04μM）。进一步的分子对接和分子动力学（MD）模拟研究表明，14e的5'-苄基可通过与Leu770，Thr768，Thr805和Leu809等疏水残基形成额外的范德华相互作用，从而与PDE2的独特疏水口袋相互作用。可能有助于增强其对PDE2的抑制作用。本文报道的这些潜在化合物以及有价值的构效关系（SAR）可能为进一步开发有效的PDE2抑制剂带来重要指导。