使用新的点击化学算法来设计D3R抑制剂作为血脑屏障的透剂
Alexander A Kovalenko1, Yuri B Porozov2,3, Ekaterina V Skorb1
1Infochemistry Scientific Center, ITMO University, Lomonosova Street 9, Saint Petersburg, 191002, Russian Federation.
Future medicinal chemistry
|July 19, 2023
概括
研究人员使用in silico点击化学策略确定了一种针对多巴胺受体D3 (D3R) 的新型化合物. 这种有前途的D3R结合剂显示大脑透率提高,有助于开发新的抗精神病药物.
科学领域:
- 药用化学 医学化学
- 计算化学计算化学
- 神经药理学神经药理学
背景情况:
- 多巴胺受体D3 (D3R) 是治疗神经系统疾病的关键标.
- 开发具有有效穿透血脑屏障 (BBB) 的选择性D3R配体对于治疗成功至关重要.
研究的目的:
- 用一种创新的in silico点击反应策略来识别新的D3R配体.
- 为了评估新设计的化合物的BBB透性和D3R亲和力.
主要方法:
- 使用in silico点击反应策略来产生潜在的D3R结合剂.
- 基于BBB透性的脑血比 (logBB) 的过化合物.
- 进行了分子动力学模拟,以评估配体-受体相互作用和稳定性.
主要成果:
- 确定了1-{4-[1-(十甲-1-) -1-H-1,2,3-三-5-] - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 作为主要候选物质的一种.
- 与乙基克洛普里德相比,鉴定的化合物显示出更高的D3R亲和力和BBB透性.
- 分子动力学模拟支持了化合物的结合亲和力和稳定性.
结论:
- 这项研究提出了一种用于D3R连接体设计的新型命中化合物.
- 建立了一个使用in silico点击化学选BBB透化合物的工作流.
- 提出的基于点击反应的算法显示了开发有效抗精神病药物的潜力.
相关概念视频
01:25Physiological Barriers
3.6K
Physiological barriers are semi-permeable cellular structures restricting drug diffusion into intracellular compartments and tissues. There are six types of physiological barriers: blood endothelial, cell membrane, blood-brain, blood-cerebrospinal fluid (CSF), blood-placenta, and blood-testis barriers.
The blood endothelial barrier is the most porous of these. It allows all small ionized, un-ionized, and lipophilic molecules to pass through the endothelial lining into the interstitial space...
The blood endothelial barrier is the most porous of these. It allows all small ionized, un-ionized, and lipophilic molecules to pass through the endothelial lining into the interstitial space...
3.6K
00:49The Blood-brain Barrier
47.6K
Overview
47.6K
01:23Factors Affecting Drug Distribution: Physiological Barriers
248
Drug distribution in the body is intricately regulated by various physiological barriers that control the passage of substances. These include the capillary endothelial barrier, the blood-brain, blood-cerebrospinal fluid, blood-placental, and blood-testis barriers.
The capillary endothelial barrier allows only smaller molecules below 600 Da (Daltons) to pass through. It also restricts drugs like heparin that are bound to blood components, limiting their movement within the bloodstream.
The...
The capillary endothelial barrier allows only smaller molecules below 600 Da (Daltons) to pass through. It also restricts drugs like heparin that are bound to blood components, limiting their movement within the bloodstream.
The...
248
01:17Pore Transport and Ion-Pair Transport
516
Pore transport and ion-pair formation are critical mechanisms for the absorption and distribution of drugs in the body.
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
516
01:25Drug-Receptor Bonds
3.0K
Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
In...
3.0K