Exploration of interaction interface of TRKβ/BDNF through fingerprint analysis to disinter potential agonists

Tyrosine Kinase beta (TRKβ), is a type I membrane receptor which plays a major role in various signalling pathways. TRKβ was found to be upregulated in various cancers and contrastingly downregulated in various neurodegenerative disorders. Hitherto, contemporary drug research is oriented towards discovery of TRKβ inhibitors, thus neglecting the development of TRKβ agonists. This research is aimed at identifying FDA approved drugs exhibiting repurposable potential as TRKβ agonists by mapping them with fingerprints of the BDNF/TRKβ interaction interface. Initially, crucial interacting residues were retrieved and a receptor grid was generated around it. TRKβ agonists were retrieved from literature search and a drug library was created for each agonist based on its structural and side effect similarities. Subsequently, molecular docking and dynamics were performed for each library to identify the drugs possessing affinity towards the binding pocket of TRKβ. The study revealed molecular interactions of Perospirone, Droperidol, Urapidil, and Clobenzorex with the crucial amino acids lining the active binding pocket of TRKβ. Subsequent network pharmacological analysis of the above drugs revealed their interactions with key proteins involved in neurotransmitter signalling pathways. Clobenzorex displayed high stability in dynamics simulation and therefore this drug is recommended for further experimental evaluations to attain better mechanistic insights and predict its implications in correcting neuropathological aberrations. This study's focus on the interaction interface between TRKβ and BDNF, combined with the utilization of fingerprint analysis for drug repurposing, contributes to our understanding of neurotrophic signalling and holds potential for identifying new therapeutic options for neurological disorders.