Klein Christian D P, Folkers G
Pharmaceutical and Medicinal Chemistry, University of the Saarland FR 8.5, PO Box 151150, D-66111 Saarbruecken, Germany.
Oncol Res. 2003;13(12):513-20. doi: 10.3727/000000003108748036.
The aim of this study is to explain the selectivity of the antiangiogenic drug fumagillin for the eukaryotic enzyme methionine aminopeptidase type II (MetAP-II, EC 3.4.11.18) over the structurally very similar MetAP-I. A homology model for the human MetAP-I is constructed and molecular dynamics simulations are performed on this model with and without a docked fumagillin molecule. These simulations are compared with analogous simulations that were performed on the experimentally determined structure of the human MetAP-II enzyme. We observe an increased flexibility of the active site histidine that is covalently modified by fumagillin in the MetAP-I enzyme. The MetAP-I active site residues, particularly the fumagillin-binding histidine, have a lower probability to be in a conformation that is prone to react with the drug than their MetAP-II counterparts. This result offers an explanation for the selectivity of fumagillin for the eukaryotic MetAP-II enzyme.
本研究的目的是解释抗血管生成药物烟曲霉素对真核酶II型蛋氨酸氨肽酶（MetAP-II，EC 3.4.11.18）相对于结构非常相似的MetAP-I的选择性。构建了人MetAP-I的同源模型，并在该模型上进行了有无对接烟曲霉素分子的分子动力学模拟。将这些模拟与在人MetAP-II酶的实验测定结构上进行的类似模拟进行比较。我们观察到在MetAP-I酶中被烟曲霉素共价修饰的活性位点组氨酸的灵活性增加。与MetAP-II对应物相比，MetAP-I活性位点残基，特别是烟曲霉素结合组氨酸，处于易于与药物反应的构象的概率较低。这一结果为烟曲霉素对真核MetAP-II酶的选择性提供了解释。
