准循环素依赖的激酶:从口袋特异性到药物选择性
Yaoguang Huang1, Wenwu Liu2, Changhao Zhao3
1School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
European journal of medicinal chemistry
|June 9, 2024
概括
开发选择性环林依赖激酶 (CDK) 调节器是具有挑战性的. 本综述探讨了结构-活性关系和口袋特征,以指导开发药物的选择性CDK抑制剂的创造.
科学领域:
- 药用化学 医学化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 循环素依赖激酶 (CDK) 是细胞循环的关键调节者,使它们成为重要的药物标.
- 开发有选择性的CDK抑制剂是具有挑战性的,因为CDK家族中激酶口袋的高度保存.
- 在CDK口袋中微妙的结构差异为实现药物选择性提供了机会.
研究的目的:
- 审查影响CDK药物开发选择性的结构-活性关系 (SARs).
- 用分子-蛋白质结合模型分析使选择性成为可能的口袋特征.
- 突出新的CDK调制器,为实现选择性提供新的策略.
主要方法:
- 分析关于CDK抑制剂及其选择性概况的现有文献.
- 检查晶体学数据以确定CDK口袋中的结构差异.
- 应用分子蛋白结合模型来理解药物向相互作用.
- 包括最近关于新型CDK调节器开发的案例研究.
主要成果:
- 利用CDK口袋中的微妙差异是实现高药物选择性的有效策略.
- 了解目标和非目标CDK结构对于选择性抑制剂设计至关重要.
- 新的CDK调制器展示了实现选择性的多种方法.
- SARs为合理的药物设计提供了一个框架,针对特定的CDK.
结论:
- 对SAR和口袋特征的详细分析对于开发选择性CDK抑制剂至关重要.
- 分子建模有助于根据结构洞察力预测和优化选择性.
- 新兴的CDK调节器扩大了针对CDK相关疾病的治疗潜力.
- 这一审查为未来开发基于CDK的向治疗提供了基础.
相关概念视频
M-Cdk Drives Transition Into Mitosis
5.6K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.6K
Inhibition of Cdk Activity
4.7K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
Targets for Drug Action: Overview
6.2K
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
6.2K
Targeted Cancer Therapies
7.5K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.5K
Positive Regulator Molecules
5.4K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.4K
Drug Discovery: Overview
7.8K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
7.8K


