酸与氨基酸的事实和谬误:在糖相对应性联结体设计的案例研究
Martin Smieško1, Roman P Jakob2, Tobias Mühlethaler3
1Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Molecules (Basel, Switzerland)
|December 31, 2025
概括
在药物设计中,用中性组取代带电组可以改变结合亲和力. 这项研究表明,胺生物异构体可以通过优化几何和形状,而不仅仅是静电,来维持或改善E-选择因子结合.
科学领域:
- 药用化学 医学化学
- 结构生物学 结构生物学
- 计算化学计算化学
背景情况:
- 用中性生物异构体取代带电组在药物发现中很常见.
- 这些替代物对结合亲和力的作用高度依赖于特定的分子环境.
- 电子选择素配体是炎症性疾病的重要标.
研究的目的:
- 为了研究一个糖仿性E-selectin连接体中用胺和异类同类物替换碳酸盐基的影响.
- 了解控制这些胺衍生物的结合亲和力的结构和能量因素.
- 探索几何和形状性质在蛋白质 - 连接体识别中的作用.
主要方法:
- 合成和特征的胺基衍生物的糖相对应的E-selectin连接体.
- 蛋白质-配体复合体的共晶结构的确定.
- 高级量子化学计算以评估电子属性.
- 分子动力学 (MD) 模拟来分析结构动力学和预组织.
- 分子力学/一般化Born表面积 (MM-GB/SA) 计算结合的自由能量分解.
主要成果:
- 与碳酸盐化合物相比,一些胺衍生物保留或改善了结合亲和力,尽管失去了一个关键的盐桥相互作用.
- 共同晶体结构显示了保留的结合姿势,其中胺碳基与Tyr48和Arg97.7相互作用.
- 量子化学计算表明,碳烯部分电荷与亲和力之间没有直接的相关性.
- 胺金字塔性与结合有中度的相关性,这表明体适合.
- MD模拟显示了高亲缘关系联体在溶液中的增强预组织,减少了性惩罚.
- MM-GB/SA分解表明,胺替代剂的轻微脂友性贡献.
结论:
- 几何和形状因素,如胺金字塔性和溶液相预组织,对于在糖相对应联体设计中驱动亲和力至关重要.
- 胺基可以作为有效的碳酸盐异体,提供细微的控制蛋白质-连接体相互作用超出简单的静电学.
- 这项研究为优化对E-selectin对抗性和其他糖仿制性标的联结体设计提供了宝贵的见解.
相关概念视频
01:11Nomenclature of Carboxylic Acid Derivatives: Amides and Nitriles
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Naming Amides
The IUPAC and common names of amides are derived from the parent carboxylic acid, by replacing the suffix “oic acid” and “ic acid,” respectively, with “amide.” In the following example, the IUPAC name ethanamide is derived from ethanoic acid, and the common name, acetamide, is obtained from acetic acid.
The IUPAC and common names of amides are derived from the parent carboxylic acid, by replacing the suffix “oic acid” and “ic acid,” respectively, with “amide.” In the following example, the IUPAC name ethanamide is derived from ethanoic acid, and the common name, acetamide, is obtained from acetic acid.
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01:28Structures of Carboxylic Acid Derivatives
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Structure of Carboxylic Acid Derivatives
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the unhybridized p...
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the unhybridized p...
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01:29Preparation of Amides
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Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
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01:19Amines to Amides: Acylation of Amines
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Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
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01:28Amides to Carboxylic Acids: Hydrolysis
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Amides can undergo either acid-catalyzed hydrolysis or base-promoted hydrolysis through a typical nucleophilic acyl substitution. Each hydrolysis requires severe conditions.
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
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01:07Acid Halides to Amides: Aminolysis
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Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
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