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

• Published in: Molecular informatics Vol. 43; no. 8; pp. e202400043 - n/a
• Main Authors: Antonijevic, Mirjana, Sopkova‐de Oliveira Santos, Jana, Dallemagne, Patrick, Rochais, Christophe
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.08.2024; Wiley-VCH
• Subjects: Algorithms; Alzheimer's disease; Brain-derived neurotrophic factor; Chemical Sciences; Communication; Drug development; Huntington's disease; Huntingtons disease; Kinases; Ligands; molecular dynamic; Molecular dynamics; Movement disorders; Neurodegenerative diseases; neurotrophins; Parkinson's disease; Pathogenesis; Physiological effects; pocket network; Protein-tyrosine kinase receptors; Questions; Receptors; TrkB receptor; TrkB receptors; Tyrosine; pocket network; TrkB receptor; molecular dynamic; neurotrophins
• ISSN: 1868-1743; 1868-1751; 1868-1751
• DOI: 10.1002/minf.202400043

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.