Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches
Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches
复制标题
DOI：
10.1021/jm060183l
复制
发表时间：
2006-08-10
影响因子：
7.3
通讯作者：
Carotti, Angelo
中科院分区：
文献类型：
--
作者：
Catto, Marco;Nicolotti, Orazio;Carotti, Angelo
设计了一系列新的3-，4-，7-多取代香豆素，并评价了它们对单胺氧化酶A和单胺氧化酶B（MAO-A和MAO-B）的抑制效力。7位的取代基由不同物理化学性质的桥组成，将苯环连接到香豆素支架。通过CoMFA-GOLPE和对接研究获得的结构-亲和力和结构-选择性关系揭示了负责所观察到的MAO-B和MAO-A抑制效力的关键物理化学相互作用，并提出了对两种酶同工型之一的高选择性的主要结构决定因素。我们的模型的预测能力通过新抑制剂的设计得到了证明，该新抑制剂在本文检查的整个系列配体中表现出出色的MAO-B亲和力（pIC（50）= 8.29）和最高的MAO-B选择性（Δ pIC（50）= 3.39）。
A new series of 3-, 4-, 7-polysubstituted coumarins have been designed and evaluated for their monoamine oxidase A and monoamine oxidase B (MAO-A and MAO-B) inhibitory potency. Substituents at position 7 consisted of a bridge of different physicochemical nature linking a phenyl ring to the coumarin scaffold. Structure-affinity and structure-selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B and MAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms. The predictive power of our models was proved with the design of a new inhibitor demonstrating an outstanding MAO-B affinity (pIC(50) = 8.29) and the highest MAO-B selectivity (Delta pIC(50) = 3.39) within the entire series of ligands examined herein.