基于药效团模型的乙酰胆碱酯酶、聚腺苷二磷酸核糖聚合酶-1双靶点分子设计研究

Pharmacophore identification of novel dual-target compounds targeting AChE and PARP-1

摘要: 本研究建立了乙酰胆碱酯酶（AChE）和聚腺苷二磷酸核糖聚合酶-1（PARP-1）抑制剂的药效团模型，设计、筛选了双靶点活性分子，并验证了其抑制活性，探讨了多靶点分子的设计策略。利用Catalyst计算机辅助药物设计软件系统，以叠合程度和构象能进行筛选，得到具有AChE、PARP-1抑制活性的双靶点结构。通过计算机预测目标分子的理化性质，得到5个优选的氨基噻唑类衍生物。将匹配的优选化合物合成后进行对AChE和PARP-1的抑制活性的实验验证。其中化合物3对AChE的抑制活性IC₅₀为（0.337 ± 0.052）μmol·L^-1，而在1 μmol·L^-1浓度下对PARP-1的抑制率为24.6%。证明药效团模型在多靶点药物设计和筛选中能起到减少盲目性和加快设计开发的作用。

Abstract: Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases.In this study, a computer-assisted strategy was applied to search for multi-target compounds bythe pharmacophore matching.This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1).Based on twopharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC₅₀ value of (0.337 ± 0.052) μmol·L^-1 and PARP-1 by 24.6% at 1 μmol·L^-1.