<br>TrkB 受体 5 域上口袋网络的发现——寻找新配体的潜在新靶点,Molecular Informatics

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TrkB 受体 5 域上口袋网络的发现——寻找新配体的潜在新靶点
Molecular Informatics ( IF 2.8 ) Pub Date : 2024-04-15 , DOI: 10.1002/minf.202400043
Mirjana Antonijevic ₁ , Jana Sopkova-de Oliveira Santos ₁ , Patrick Dallemagne ₁ , Christophe Rochais ₁

Affiliation

神经营养蛋白酪氨酸激酶受体 - TrkB 在阿尔茨海默病、帕金森病、亨廷顿病等多种神经退行性疾病的发病机制中的重要作用已得到充分描述。这不足为奇，因为在生理条件下，一旦被脑源性神经营养因子 (BDNF) 和神经营养蛋白-4/5 (NT-4/5) 激活，TrkB 受体就会促进神经元存活、分化和突触功能。考虑到 TrkB 受体的天然配体是大蛋白质，发现能够模拟其作用的小分子是一个挑战。尽管与 BDNF 或 NT-4/5 相互作用的受体表面是已知的，但始终存在哪个口袋和交互负责激活它的问题。为了回答这个具有挑战性的问题，我们使用了分子动力学（MD）模拟和Pocketron算法，这使我们能够首次检测到受体相互作用域（d5）中存在的口袋网络；描述他们并了解他们如何相互沟通。这一新发现为我们提供了受体的潜在新领域，可以在新配体的开发中靶向并用于基于结构的药物设计方法。

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Discovery of a pocket network on the domain 5 of the TrkB receptor – A potential new target in the quest for the new ligands

The important role that the neurotrophin tyrosine kinase receptor ‐ TrkB has in the pathogenesis of several neurodegenerative conditions such are Alzheimer's disease, Parkinson's disease, Huntington's disease, has been well described. This shouldn't be a surprise, since in the physiological conditions, once activated by brain‐derived neurotrophic factor (BDNF) and neurotrophin‐4/5 (NT‐4/5), the TrkB receptor promotes neuronal survival, differentiation and synaptic function. Considering that the natural ligands for TrkB receptor are large proteins, it is a challenge to discover small molecule capable to mimic their effects.Even though, the surface of receptor that is interacting with BDNF or NT‐4/5 is known, there was always a question which pocket and interaction is responsible for activation of it. In order to answer this challenging question, we have used molecular dynamic (MD) simulations and Pocketron algorithm which enabled us to detect, for the first time, a pocket network existing in the interacting domain (d5) of the receptor; to describe them and to see how they are communicating with each other. This new discovery gave us potential new areas on receptor that can be targeted and used for structure‐based drug design approach in the development of the new ligands.

更新日期：2024-04-15

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