甲基转移酶的过渡状态类似物
Niusha Mahmoodi1, Rajesh K Harijan1, Vern L Schramm1
1Department of Biochemistry, Albert Einstein College of Medicine, New York, New York 10461, United States.
Journal of the American Chemical Society
|July 25, 2020
概括
甲胺N-甲基转移酶 (PNMT) 抑制剂的设计是为了模仿其过渡状态. 一种新型抑制剂显示纳米分子亲和力,为PNMT相关疾病提供新的治疗潜力.
科学领域:
- 生物化学
- 酵素学
- 药理学
背景情况:
- 甲胺N-甲基转移酶 (PNMT) 对于甲胺合成至关重要,产生上腺素.
- 上腺素在血压,呼吸和神经退行,包括阿尔茨海默病中起作用.
- PNMT的甲基转移反应通过限制速率的SN2过渡状态进行.
研究的目的:
- 设计和合成人类PNMT (hPNMT) 的新型过渡状态 (TS) 模拟抑制剂.
- 描述这些抑制剂的结合亲和力和机制.
- 探索TS类似物作为强大的酶抑制剂的潜力.
主要方法:
- 模仿hPNMT TS几何和电子特性的分子设计.
- 设计TS模拟抑制剂的化学合成.
- 动力特征,包括Ki的确定.
- 用于结合分析的异热定位热量计 (ITC).
- 抑制剂-hPNMT复合物的结构分析.
主要成果:
- 一种新型的抑制性支架已成功合成.
- 抑制剂 (化合物3) 具有12. 0nM的Ki的紧密结合亲和力.
- 这代表了一种甲基转移酶TS模拟抑制剂的纳米分子亲和力.
- ITC发现了由驱动的负合作结合.
- 结构数据显示,抑制剂3既占据了辅因子 (SAM) 的结合点,也占据了基质 (norepinephrine) 的结合点.
结论:
- 过渡状态的模拟设计产生了强大的hPNMT抑制剂.
- 该抑制剂的纳米分子亲和力和结合模式提供了一个有前途的新疗法.
- 这项工作促进了甲基转移酶的特异性抑制剂的开发.
相关概念视频
Adrenergic Agonists: Indirect-Acting Agents
2.4K
Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral...
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral...
2.4K
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
3.7K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
3.7K
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
810
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
810
Indirect-Acting Cholinergic Agonists: Mechanism of Action
2.4K
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
2.4K
Drugs Affecting Neurotransmitter Synthesis
2.0K
Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase,...
2.0K
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
1.8K
Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
The direct-acting...
1.8K


