超大图书馆对接用于发现新化学类型
Jiankun Lyu1,2, Sheng Wang3,4, Trent E Balius1
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Nature
|February 8, 2019
概括
通过基于结构的对接, 研究人员发现了强大的AmpCβ-乳糖酶抑制剂和D4多巴胺受体配体,扩大了药物发现的可能性.
科学领域:
- 医学化学
- 计算化学
- 药物发现
背景情况:
- 庞大的化学图书馆对于药物发现至关重要,
- 按需合成提供了新化学实体的途径.
研究的目的:
- 调查基于结构的对接对于大型,按需制作的复合库的可行性.
- 确定AmpCβ- 乳糖酶的新兴抑制剂和D4多巴胺受体的配体.
主要方法:
- 基于结构的对接模拟在170万个按需制造的化合物上进行.
- 合成并对AmpC和D4多巴胺受体进行了测试.
- 使用X射线结晶学验证对接预测.
主要成果:
- 发现了一种新型的AmpCβ- 乳糖酶抑制剂,其中一种被优化为77nM的强度.
- 发现了453,000个潜在的D4多巴胺受体连接体,其中包括81种新的化学类型.
- 发现了30种具有微小分子活性的化合物,包括180 pM亚型选择性D4多巴胺受体激动剂.
结论:
- 基于结构的大型按需库的对接是化学空间扩张的有效策略.
- 这种方法成功地确定了治疗标的强效抑制剂和新体.
- 这种方法为加速药物发现提供了一个强大的平台.
相关概念视频
Subatomic Particles
112.9K
Dalton was only partially correct about the particles that make up matter. All matter is composed of atoms, and atoms are composed of three smaller subatomic particles: protons, neutrons, and electrons. These three particles account for the mass and the charge of an atom.
112.9K
Free Energy
52.0K
Free energy—abbreviated as G for the scientist Gibbs who discovered it—is a measurement of useful energy that can be extracted from a reaction to do work. It is the energy in a chemical reaction that is available after entropy is accounted for. Reactions that take in energy are considered endergonic and reactions that release energy are exergonic. Plants carry out endergonic reactions by taking in sunlight and carbon dioxide to produce glucose and oxygen. Animals, in turn, break...
52.0K
Groupthink
50.1K
When in group settings, we are often influenced by the thoughts, feelings, and behaviors around us. Groupthink is another phenomenon of conformity where modification of the opinions of members in a group aligns with what they believe is the group consensus (Janis, 1972). In such situations, the group often takes action that individuals would not perform outside the group setting because groups make more extreme decisions than individuals do. Moreover, groupthink can hinder opposing trains of...
50.1K
Gene Families
9.9K
Gene families consist of groups of genes proposed to have originated from a common ancestor. Typically these arise through events in which a gene or genes are mistakenly duplicated during cell division. Unlike their parent genes (which are subject to selection pressure to maintain function), these gene copies do not need to preserve their sequences and may evolve at a relatively faster rate.
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
9.9K
Elements: Chemical Symbols and Isotopes
125.8K
A chemical symbol is an abbreviation used to indicate an element or an atom of an element. For example, the symbol for mercury is Hg. The same symbol is used to indicate one atom of mercury (microscopic domain) or to label a container of many atoms of the element mercury (macroscopic domain).
Some symbols are derived from the common English name of the element; others are abbreviations of the name in another language — Latin, Greek or German. For example, the symbol for aluminum (common name)...
Some symbols are derived from the common English name of the element; others are abbreviations of the name in another language — Latin, Greek or German. For example, the symbol for aluminum (common name)...
125.8K
Longitudinal Research
13.3K
Sometimes we want to see how people change over time, as in studies of human development and lifespan. When we test the same group of individuals repeatedly over an extended period of time, we are conducting longitudinal research. Longitudinal research is a research design in which data-gathering is administered repeatedly over an extended period of time. For example, we may survey a group of individuals about their dietary habits at age 20, retest them a decade later at age 30, and then again...
13.3K


