Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand x-ray crystal structure

Ghosh A.K.; Venkateswara Rao K.; Yadav N.D.; Anderson D.D.; Gavande N.; Huang X.; Terzyan S.; Tang J.

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Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand x-ray crystal structure

机译：高选择性β-分泌酶抑制剂的基于结构的设计：合成，生物学评估和蛋白质配体x射线晶体结构

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The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S _1′ active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K _i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

机译：描述了基于结构的设计，合成和X射线结构的蛋白质和配体复合物的异常有效和选择性的β分泌酶抑制剂。抑制剂经过专门设计，可与S _1'活性位点残基相互作用，以提供对memapsin 1和组织蛋白酶D的选择性。抑制剂5具有超强的抑制活性（K _i = 17 pM）和对BACE 2的高选择性（> 7000倍））和组织蛋白酶D（> 250000倍）。蛋白质-配体晶体结构揭示了对这些选择性的重要分子认识。这些相互作用可作为设计对生理上重要的天冬氨酸蛋白酶的选择性的重要指导。

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《Journal of Medicinal Chemistry》 |2012年第21期|共13页
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Ghosh A.K.; Venkateswara Rao K.; Yadav N.D.; Anderson D.D.; Gavande N.; Huang X.; Terzyan S.; Tang J.;
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1. Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand x-ray crystal structure [J] . Ghosh A.K., Venkateswara Rao K., Yadav N.D., Journal of Medicinal Chemistry . 2012,第21期

机译：高选择性β-分泌酶抑制剂的基于结构的设计：合成，生物学评估和蛋白质配体x射线晶体结构
2. Design,Synthesis and X-ray Structure of Protein-Ligand Complexes;Important Insight into Selectivity of Memapsin 2(beta-Secretase)Inhibitors [J] . Arun K.Ghosh, Nagaswamy Kumaragurubaran, Lin Hong, Journal of the American Chemical Society . 2006,第16期

机译：蛋白质-配体配合物的设计，合成及X射线结构；对Memapsin 2（β-分泌酶）抑制剂选择性的重要了解
3. Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: Synthesis, biological evaluation, and protein-ligand X-ray crystal structure [J] . Ghosh A.K., Chapsal B.D., Parham G.L., Journal of Medicinal Chemistry . 2011,第16期

机译：以C3-取代的六氢环戊呋喃基氨基甲酸酯为P2-配体的HIV-1蛋白酶抑制剂的设计：合成，生物学评估和蛋白配体X射线晶体结构
4. A highly selective cell permeable peptide inhibitor of proprotein convertase 1:design,synthesis and biological evaluation in cellular PC1-mediated proteolysis [C] . Ajoy Basak, Peter Koch, Marcel Dupelle, the International Peptide Symposium . 2001

机译：一种高精度的细胞渗透肽抑制作用的ProProtein转化酶1：细胞PC1介导的蛋白水解中的设计，合成和生物学评估
5. NG-nitro-L-arginine-containing peptidomimetics as selective neuronal nitric oxide synthase inhibitors. Structure-based design, synthesis, and biological evaluation and approaches toward enhanced CNS activity. [D] . Seo, Jiwon. 2006

机译：含NG-硝基-L-精氨酸的拟肽作为选择性神经元一氧化氮合酶抑制剂。基于结构的设计，合成和生物学评估以及增强CNS活性的方法。
6. Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis Biological Evaluation and Protein-Ligand X-ray Crystal Structure [O] . Arun K. Ghosh, Kalapala Venkateswara Rao, Navnath D. Yadav, -1

机译：高选择性β分泌酶抑制剂的基于结构的设计合成生物评价和蛋白 - 配体X射线晶体结构
7. Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure [O] . Arun K. Ghosh, Kalapala Venkateswara Rao, Navnath D. Yadav, 2012

机译：基于结构的高选择性β-分泌酶抑制剂的设计：合成，生物学评价和蛋白质 - 配体X射线晶体结构

Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand x-ray crystal structure

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