基于结构的 BACE2 发现平台和选择性 BACE 抑制剂的开发。
A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.
出版信息
ACS Chem Neurosci. 2021 Feb 17;12(4):581-588. doi: 10.1021/acschemneuro.0c00629. Epub 2021 Feb 5.
Abstract
The ability to perform routine structure-guided drug design for selective BACE inhibitors has been limited because of the lack of robust platform for BACE2 expression, purification, and crystallization. To overcome this limitation, we developed a platform that produces 2-3 mg of pure BACE2 protein per liter of culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound was found to potently inhibit BACE 1 ( = 5 nM) with a selectivity of 214-fold over BACE2. The X-ray crystal structures of unbound BACE2 (2.2 Å) and BACE2 bound to compound (3.0 Å and = 7 nM) were determined and compared to the X-ray structures of BACE1 revealing the S1-S3 subsite as a selectivity determinant. This platform should enable a more rapid development of new and selective BACE inhibitors for the treatment of Alzheimer's disease or type II diabetes.
摘要
由于缺乏用于 BACE2 表达、纯化和结晶的稳健平台，因此进行常规的基于结构的药物设计来选择性抑制 BACE 抑制剂的能力受到限制。为了克服这一限制，我们开发了一个平台，可从每升培养物中生产出 2-3 毫克的纯 BACE2 蛋白，我们使用该蛋白来设计强效且选择性抑制 BACE1 而非 BACE2 的大环化合物。发现化合物 对 BACE1 具有很强的抑制作用（ = 5 nM），对 BACE2 的选择性为 214 倍。确定了未结合的 BACE2（2.2 Å）和与化合物 结合的 BACE2（3.0 Å 和 = 7 nM）的 X 射线晶体结构，并与 BACE1 的 X 射线结构进行了比较，揭示了 S1-S3 亚基作为选择性决定因素。该平台应能更快速地开发出用于治疗阿尔茨海默病或 2 型糖尿病的新型和选择性 BACE 抑制剂。
相似文献
1
A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.基于结构的 BACE2 发现平台和选择性 BACE 抑制剂的开发。
ACS Chem Neurosci. 2021 Feb 17;12(4):581-588. doi: 10.1021/acschemneuro.0c00629. Epub 2021 Feb 5.
2
Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies.高选择性和强效的人β-分泌酶 2（BACE2）抑制剂用于 2 型糖尿病：设计、合成、X 射线结构和构效关系研究。
ChemMedChem. 2019 Mar 5;14(5):545-560. doi: 10.1002/cmdc.201800725. Epub 2019 Feb 5.
3
Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.基于结构的选择性β-淀粉样前体蛋白裂解酶 1（BACE1）抑制剂的设计：针对瓣区以获得对 BACE2 的选择性。
J Med Chem. 2019 May 23;62(10):5080-5095. doi: 10.1021/acs.jmedchem.9b00309. Epub 2019 May 13.
4
A series of molecular modeling techniques to reveal selective mechanisms of inhibitors to β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2).一系列分子建模技术，揭示β-淀粉样前体蛋白裂解酶 1（BACE1）和β-淀粉样前体蛋白裂解酶 2（BACE2）抑制剂的选择性机制。
J Biomol Struct Dyn. 2021 May;39(8):2824-2837. doi: 10.1080/07391102.2020.1754917. Epub 2020 Apr 20.
5
Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor.人源β-分泌酶2（BACE2）与羟乙胺过渡态抑制剂复合物的晶体结构
J Mol Biol. 2006 Jan 13;355(2):249-61. doi: 10.1016/j.jmb.2005.10.027. Epub 2005 Nov 8.
6
New Highly Selective BACE1 Inhibitors and Their Effects on Dendritic Spine Density In Vivo.新型高选择性 BACE1 抑制剂及其对体内树突棘密度的影响。
Int J Mol Sci. 2023 Jul 31;24(15):12283. doi: 10.3390/ijms241512283.
7
Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.通过多次短分子动力学模拟和自由能预测揭示抑制剂对 BACE1 和 BACE2 的结合选择性的分子机制。
ACS Chem Neurosci. 2019 Oct 16;10(10):4303-4318. doi: 10.1021/acschemneuro.9b00348. Epub 2019 Oct 2.
8
1,3-Oxazines as BACE1 and/or BACE2 inhibitors: a patent evaluation (WO2012156284).1,3-恶嗪类作为 BACE1 和/或 BACE2 抑制剂：专利评估（WO2012156284）。
Expert Opin Ther Pat. 2013 Aug;23(8):1069-73. doi: 10.1517/13543776.2013.818134. Epub 2013 Jul 10.
9
A comparative molecular dynamics study on BACE1 and BACE2 flap flexibility.关于β-分泌酶1（BACE1）和β-分泌酶2（BACE2）活性中心灵活区的比较分子动力学研究
J Recept Signal Transduct Res. 2016 Oct;36(5):505-14. doi: 10.3109/10799893.2015.1130058. Epub 2016 Jan 24.
10
Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective β-Secretase (BACE1) Inhibitors over BACE2.基于结构的方法利用显式水分子提高选择性：选择性β-分泌酶（BACE1）抑制剂对 BACE2 的发现。
J Med Chem. 2021 Mar 25;64(6):3075-3085. doi: 10.1021/acs.jmedchem.0c01858. Epub 2021 Mar 15.
引用本文的文献
1
Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: current and future perspective.阿尔茨海默病治疗方法的最新进展：现状与未来展望。
RSC Med Chem. 2024 Dec 6;16(2):652-693. doi: 10.1039/d4md00630e. eCollection 2025 Feb 19.
2
The Roles of the Amyloid Beta Monomers in Physiological and Pathological Conditions.淀粉样β单体在生理和病理条件下的作用。
Biomedicines. 2023 May 10;11(5):1411. doi: 10.3390/biomedicines11051411.
3
Clinical antidiabetic medication used in Alzheimer's disease: From basic discovery to therapeutics development.用于阿尔茨海默病的临床抗糖尿病药物：从基础发现到治疗药物开发。
Front Aging Neurosci. 2023 Feb 10;15:1122300. doi: 10.3389/fnagi.2023.1122300. eCollection 2023.
本文引用的文献
1
Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations.通过多重复制加速分子动力学模拟解析二硫键对抑制剂与β-淀粉样蛋白裂解酶1结合的影响
ACS Chem Neurosci. 2020 Jun 17;11(12):1811-1826. doi: 10.1021/acschemneuro.0c00234. Epub 2020 Jun 8.
2
Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors.开发用于 BACE1 抑制剂的高效酶生产和基于结构的发现平台。
Biochemistry. 2019 Nov 5;58(44):4424-4435. doi: 10.1021/acs.biochem.9b00714. Epub 2019 Oct 22.
3
Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.通过多次短分子动力学模拟和自由能预测揭示抑制剂对 BACE1 和 BACE2 的结合选择性的分子机制。
ACS Chem Neurosci. 2019 Oct 16;10(10):4303-4318. doi: 10.1021/acschemneuro.9b00348. Epub 2019 Oct 2.
4
Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.基于结构的选择性β-淀粉样前体蛋白裂解酶 1（BACE1）抑制剂的设计：针对瓣区以获得对 BACE2 的选择性。
J Med Chem. 2019 May 23;62(10):5080-5095. doi: 10.1021/acs.jmedchem.9b00309. Epub 2019 May 13.
5
Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies.高选择性和强效的人β-分泌酶 2（BACE2）抑制剂用于 2 型糖尿病：设计、合成、X 射线结构和构效关系研究。
ChemMedChem. 2019 Mar 5;14(5):545-560. doi: 10.1002/cmdc.201800725. Epub 2019 Feb 5.
6
Design of Potent and Highly Selective Inhibitors for Human β-Secretase 2 (Memapsin 1), a Target for Type 2 Diabetes.强效且高选择性的人β-分泌酶2（膜内天冬氨酸蛋白酶1）抑制剂的设计，2型糖尿病的一个靶点
Chem Sci. 2016 May 1;7(5):3117-3122. doi: 10.1039/C5SC03718B. Epub 2016 Feb 4.
7
Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.药理学抑制β-分泌酶1（BACE1）和β-分泌酶2（BACE2）可通过抑制小鼠中PMEL17的加工过程诱导毛发色素脱失。
Sci Rep. 2016 Feb 25;6:21917. doi: 10.1038/srep21917.
8
Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate.鉴定人胰岛淀粉样多肽为β-分泌酶2（BACE2）的底物。
PLoS One. 2016 Feb 3;11(2):e0147254. doi: 10.1371/journal.pone.0147254. eCollection 2016.
9
A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.一种新型β-分泌酶（BACE）抑制剂NB-360在APP转基因小鼠中显示出卓越的药理学特性，并能显著降低β-淀粉样蛋白水平和神经炎症。
Mol Neurodegener. 2015 Sep 3;10:44. doi: 10.1186/s13024-015-0033-8.
10
Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic β-cells.抑制β-分泌酶2（BACE2）可抵消人胰岛淀粉样多肽（hIAPP）诱导的胰腺β细胞胰岛素分泌缺陷。
FASEB J. 2015 Jan;29(1):95-104. doi: 10.1096/fj.14-255489. Epub 2014 Oct 23.
Zotero 插件