分子内氢键：提高神经型一氧化氮合酶抑制剂生物利用度的一种潜在策略。
Intramolecular hydrogen bonding: a potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase.
机构信息
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
出版信息
Bioorg Med Chem. 2012 Apr 1;20(7):2435-43. doi: 10.1016/j.bmc.2012.01.037. Epub 2012 Feb 7.
Abstract
Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.
摘要
选择性神经元型一氧化氮合酶（nNOS）抑制剂在治疗多种神经退行性疾病方面具有治疗应用。在这里，我们报告了一系列抑制剂的合成和评估，这些抑制剂旨在通过分子内氢键增加细胞膜通透性。它们的效力在纯化酶和基于细胞的测定中进行了检查；对这些结果的比较表明，两种新的抑制剂与以前的类似物相比，膜通透性显著增加。NMR 光谱提供了两种抑制剂在生理条件下分子内氢键的证据。抑制剂在 nNOS 活性部位的晶体结构证实了预测的非分子内氢键结合模式。分子内氢键可能是一种有效的方法，可在不影响靶蛋白结合的情况下增加细胞膜通透性。
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本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
Improved synthesis of chiral pyrrolidine inhibitors and their binding properties to neuronal nitric oxide synthase.手性吡咯烷抑制剂的改进合成及其与神经元型一氧化氮合酶的结合特性。
J Med Chem. 2011 Sep 22;54(18):6399-403. doi: 10.1021/jm200411j. Epub 2011 Aug 22.
3
Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives.通过设计和合成吡咯烷甲基 2-氨基吡啶衍生物来探索神经元型一氧化氮合酶的活性部位。
J Med Chem. 2010 Nov 11;53(21):7804-24. doi: 10.1021/jm100947x.
4
Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.强效、高选择性、口服生物可利用的神经型一氧化氮合酶的全氟二氟代单正离子抑制剂。
J Am Chem Soc. 2010 Oct 13;132(40):14229-38. doi: 10.1021/ja106175q.
5
Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.外周但关键：一个疏水性口袋（Tyr(706)、Leu(337)和 Met(336)），可强效且选择性抑制神经元型一氧化氮合酶。
Bioorg Med Chem Lett. 2010 Nov 1;20(21):6258-61. doi: 10.1016/j.bmcl.2010.08.096. Epub 2010 Aug 26.
6
Structure-based design, synthesis, and biological evaluation of lipophilic-tailed monocationic inhibitors of neuronal nitric oxide synthase.基于结构的设计、合成及亲脂性尾式单正离子神经元型一氧化氮合酶抑制剂的生物学评价。
Bioorg Med Chem. 2010 Sep 1;18(17):6526-37. doi: 10.1016/j.bmc.2010.06.074. Epub 2010 Jul 1.
7
Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.用于抗恰加斯病药物发现的癌症药物临床候选物替匹法尼的第二代类似物。
J Med Chem. 2010 May 27;53(10):3887-98. doi: 10.1021/jm9013136.
8
Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model.意想不到的一氧化氮合酶抑制剂结合模式可有效预防动物模型中的脑瘫表型。
J Am Chem Soc. 2010 Apr 21;132(15):5437-42. doi: 10.1021/ja910228a.
9
Intramolecular hydrogen bonding in medicinal chemistry.分子内氢键在药物化学中的作用。
J Med Chem. 2010 Mar 25;53(6):2601-11. doi: 10.1021/jm100087s.
10
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Bioorg Med Chem Lett. 2010 Jan 15;20(2):554-7. doi: 10.1016/j.bmcl.2009.11.086. Epub 2009 Nov 22.
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