Ghosh Arun K, Kumaragurubaran Nagaswamy, Hong Lin, Lei Hui, Hussain Khaja Azhar, Liu Chun-Feng, Devasamudram Thippeswamy, Weerasena Vajira, Turner Robert, Koelsch Gerald, Bilcer Geoffrey, Tang Jordan
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
J Am Chem Soc. 2006 Apr 26;128(16):5310-1. doi: 10.1021/ja058636j.
Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.
本文描述了基于结构的胃蛋白酶2蛋白-配体复合物的设计、合成及X射线晶体结构。这些抑制剂经专门设计，可与S2和S3活性位点残基相互作用，从而对胃蛋白酶1和组织蛋白酶D具有选择性。抑制剂6对胃蛋白酶2表现出极强的抑制活性，对胃蛋白酶1（>3800倍）和组织蛋白酶D（>2500倍）具有选择性。蛋白质-配体晶体结构揭示了胃蛋白酶2的S2和S3活性位点中的协同相互作用。这些相互作用可能为设计对胃蛋白酶1和组织蛋白酶D具有选择性的抑制剂提供重要指导。
