药物化学中的分子内氢键预期
Intramolecular Hydrogen Bond Expectations in Medicinal Chemistry.
作者信息
Giordanetto Fabrizio, Tyrchan Christian, Ulander Johan
机构信息
D.E. Shaw Research , 120W 45th Street, New York, New York 10036, United States.
Medicinal Chemistry, Respiratory and Inflammation, Innovative Medicines and Early Development Biotech Unit, Astrazeneca, Mölndal , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
出版信息
ACS Med Chem Lett. 2017 Jan 18;8(2):139-142. doi: 10.1021/acsmedchemlett.7b00002. eCollection 2017 Feb 9.
Abstract
Design strategies centered on intramolecular hydrogen bonds are sometime used in drug discovery, but their general applicability has not been addressed beyond scattered examples or circumstantial evidence. A total of 1053 matched molecular pairs where only one of the two molecules is able to form an intramolecular hydrogen bond via monatomic transformations have been identified across the ChEMBL database. These pairs were used to investigate the effect of intramolecular hydrogen bonds on biological activity. While cases of extreme, conflicting variation of effect emerge, the mean biological activity difference for a pair is close to zero and does not exceed ±0.5 log biological activity for over 50% of the analyzed sample.
摘要
以分子内氢键为核心的设计策略有时会用于药物研发，但除了一些零散的例子或间接证据外，其普遍适用性尚未得到充分探讨。在ChEMBL数据库中，总共识别出1053对匹配分子对，其中两个分子中只有一个能够通过单原子转化形成分子内氢键。这些分子对被用于研究分子内氢键对生物活性的影响。虽然出现了一些极端的、相互矛盾的效应变化情况，但对于一对分子而言，其平均生物活性差异接近零，并且在超过50%的分析样本中，生物活性差异不超过±0.5 log生物活性。
相似文献
1
Intramolecular Hydrogen Bond Expectations in Medicinal Chemistry.药物化学中的分子内氢键预期
ACS Med Chem Lett. 2017 Jan 18;8(2):139-142. doi: 10.1021/acsmedchemlett.7b00002. eCollection 2017 Feb 9.
2
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.
3
Two-way effects between hydrogen bond and intramolecular resonance effect: an ab initio study on complexes of formamide and its derivatives with water.氢键与分子内共振效应的双向作用：甲酰胺及其衍生物与水形成的配合物的从头算研究
J Phys Chem A. 2008 Jun 19;112(24):5436-47. doi: 10.1021/jp712052e. Epub 2008 May 27.
4
Interplay between hydrogen-bond formation and multicenter pi-electron delocalization: intramolecular hydrogen bonds.氢键形成与多中心π电子离域之间的相互作用：分子内氢键
J Phys Chem A. 2008 Oct 23;112(42):10689-96. doi: 10.1021/jp805084n. Epub 2008 Sep 27.
5
Oligo(p-phenylene-ethynylene)s with backbone conformation controlled by competitive intramolecular hydrogen bonds.具有由竞争分子内氢键控制的骨架构象的寡聚（对苯撑乙炔）。
Chemistry. 2011 Jun 14;17(25):7087-94. doi: 10.1002/chem.201003603. Epub 2011 May 9.
6
Nuclear magnetic resonance spectroscopy and molecular modeling reveal that different hydrogen bonding patterns are possible for G.U pairs: one hydrogen bond for each G.U pair in r(GGCGUGCC)(2) and two for each G.U pair in r(GAGUGCUC)(2).核磁共振光谱和分子模型表明，G.U碱基对可能存在不同的氢键模式：在r(GGCGUGCC)(2)中每个G.U碱基对有一个氢键，而在r(GAGUGCUC)(2)中每个G.U碱基对有两个氢键。
Biochemistry. 2000 Aug 1;39(30):8970-82.
7
Role of intramolecular and intermolecular hydrogen bonding in both singlet and triplet excited states of aminofluorenones on internal conversion, intersystem crossing, and twisted intramolecular charge transfer.分子内和分子间氢键在氨基芴酮的单重态和三重态激发态中的内转换、系间穿越和扭曲分子内电荷转移中的作用。
J Phys Chem A. 2009 Dec 31;113(52):14329-35. doi: 10.1021/jp903200x.
8
Statistical and molecular dynamics studies of buried waters in globular proteins.球状蛋白质中埋藏水的统计与分子动力学研究。
Proteins. 2005 Aug 15;60(3):450-63. doi: 10.1002/prot.20511.
9
Universal prediction of intramolecular hydrogen bonds in organic crystals.有机晶体中分子内氢键的通用预测
Acta Crystallogr B. 2010 Apr;66(Pt 2):237-52. doi: 10.1107/S0108768110003988. Epub 2010 Mar 16.
10
The effect of intramolecular interactions on hydrogen bond acidity.分子内相互作用对氢键酸度的影响。
Org Biomol Chem. 2003 Apr 21;1(8):1419-24. doi: 10.1039/b300598d.
引用本文的文献
1
N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group.N-(3-羟基苯基)-3,8-二氮杂双环辛烷作为阿片受体探针。1. 酚羟基的研究。
Eur J Med Chem. 2025 Nov 15;298:117991. doi: 10.1016/j.ejmech.2025.117991. Epub 2025 Jul 23.
2
In vitro larvicidal activity of selected azabenzimidazole and diarylquinoline derivatives against Anopheles gambiae and in silico mechanistic analysis.所选氮杂苯并咪唑和二芳基喹啉衍生物对冈比亚按蚊的体外杀幼虫活性及计算机机制分析
Mol Divers. 2025 Apr 10. doi: 10.1007/s11030-025-11189-4.
3
Unveiling Repulsion in Intramolecular H-Bonded Systems.揭示分子内氢键体系中的斥力
J Am Chem Soc. 2025 Apr 16;147(15):12381-12385. doi: 10.1021/jacs.5c00385. Epub 2025 Apr 7.
4
In Silico Approach: Anti-Tuberculosis Activity of Caespitate in the H37Rv Strain.计算机模拟方法：丛生草提取物对H37Rv菌株的抗结核活性
Curr Issues Mol Biol. 2024 Jun 27;46(7):6489-6507. doi: 10.3390/cimb46070387.
5
Hydrogen Bonding Drives Helical Chirality via 10-Membered Rings in Dipeptide Conjugates of Ferrocene-1,1'-Diamine.二茂铁-1,1'-二胺二肽轭合物中环十肽诱导氢键螺旋手性。
Int J Mol Sci. 2022 Oct 13;23(20):12233. doi: 10.3390/ijms232012233.
6
Lifetime distribution of clusters in binary mixtures involving hydrogen bonding liquids.涉及氢键液体的二元混合物中团簇的寿命分布。
Sci Rep. 2022 Jun 1;12(1):9120. doi: 10.1038/s41598-022-12779-0.
7
Chemical Analysis and Bioactivity of Essential Oil of and Safrole Derivatives against Oomycete Fish Pathogens.精油和黄樟素衍生物的化学分析及生物活性对卵菌鱼类病原菌的抑制作用
Molecules. 2021 Oct 29;26(21):6551. doi: 10.3390/molecules26216551.
8
Introduction to "Intramolecular Hydrogen Bonding 2018".“2018 年分子内氢键”简介。
Molecules. 2019 Aug 7;24(16):2858. doi: 10.3390/molecules24162858.
9
Energetics in Epoxide, Thiirane, Aziridine and Phosphirane Containing Cyclopentanols: Effects of Intramolecular OH⋯O, S, N and P Contacts.含环氧乙烷、硫杂环戊烷、氮杂环丙烷和磷杂环戊烷的环戊醇的热力学性质：分子内 OH⋯O、S、N 和 P 接触的影响。
Molecules. 2019 Jul 10;24(14):2523. doi: 10.3390/molecules24142523.
10
Assessing Parameter Suitability for the Strength Evaluation of Intramolecular Resonance Assisted Hydrogen Bonding in -Carbonyl Hydroquinones.评估 - 羰基对苯二酚分子内共振氢键强度评估中参数适用性。
Molecules. 2019 Jan 14;24(2):280. doi: 10.3390/molecules24020280.
本文引用的文献
1
Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds.大环化合物的被动膜通透性可由环外酰胺键控制。
J Med Chem. 2016 Jun 9;59(11):5368-76. doi: 10.1021/acs.jmedchem.6b00222. Epub 2016 May 19.
2
Stable Blue Phosphorescence Iridium(III) Cyclometalated Complexes Prompted by Intramolecular Hydrogen Bond in Ancillary Ligand.辅助配体中分子内氢键引发的稳定蓝色磷光铱（III）环金属化配合物
Inorg Chem. 2016 Apr 4;55(7):3324-31. doi: 10.1021/acs.inorgchem.5b02511. Epub 2016 Mar 18.
3
Design and optimization of selective azaindole amide M1 positive allosteric modulators.选择性氮杂吲哚酰胺M1正向变构调节剂的设计与优化
Bioorg Med Chem Lett. 2016 Jan 15;26(2):650-655. doi: 10.1016/j.bmcl.2015.11.053. Epub 2015 Nov 17.
4
Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation.新型5-(3,4,5-三甲氧基苯甲酰基)-4-氨基嘧啶衍生物的设计与合成：作为强效和选择性磷酸二酯酶5抑制剂通过分子内氢键形成假环进行骨架跃迁
Bioorg Med Chem Lett. 2014 Nov 15;24(22):5175-80. doi: 10.1016/j.bmcl.2014.09.082. Epub 2014 Oct 2.
5
Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.向强效和选择性JAK3抑制剂的骨架跃迁：新型C-5取代吡咯并吡嗪的发现
Bioorg Med Chem Lett. 2014 Nov 1;24(21):4969-75. doi: 10.1016/j.bmcl.2014.09.031. Epub 2014 Sep 21.
6
Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.杂芳基吡唑芳基磺酰胺类作为变构 C 型趋化因子受体 4（CCR4）拮抗剂的先导化合物的鉴定和构效关系研究。
Org Biomol Chem. 2014 Mar 21;12(11):1779-92. doi: 10.1039/c3ob42443j.
7
How hydrogen bonds impact P-glycoprotein transport and permeability.氢键如何影响 P-糖蛋白的转运和通透性。
Bioorg Med Chem Lett. 2012 Nov 1;22(21):6540-8. doi: 10.1016/j.bmcl.2012.08.059. Epub 2012 Aug 23.
8
Intramolecular hydrogen bonding: a potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase.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。
Bioorg Med Chem. 2012 Apr 1;20(7):2435-43. doi: 10.1016/j.bmc.2012.01.037. Epub 2012 Feb 7.
9
Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.基于结构的新型 II 型 c-Met 抑制剂设计：1. 吡唑酮类衍生物的鉴定。
J Med Chem. 2012 Mar 8;55(5):1858-67. doi: 10.1021/jm201330u. Epub 2012 Feb 24.
10
ChEMBL: a large-scale bioactivity database for drug discovery.ChEMBL：用于药物发现的大型生物活性数据库。
Nucleic Acids Res. 2012 Jan;40(Database issue):D1100-7. doi: 10.1093/nar/gkr777. Epub 2011 Sep 23.
Zotero 插件