Discovery of Bavachin as a Dual Trk-A/Trk-B Agonist via Integrated Computational Screening and Experimental Validation
- 1Widener University
Abstract
Neurotrophins regulate neuronal survival, differentiation, and synaptic plasticity through activation of tropomyosin receptor kinase (Trk) receptors, and their dysregulation is strongly implicated in neurodegenerative disorders, including Alzheimer's disease. However, the therapeutic application of recombinant neurotrophins remains limited by poor bioavailability, rapid degradation, and inadequate blood brain barrier permeability. Here, we report the discovery of Bavachin as a dual Trk-A/Trk-B neurotrophin mimetic via an integrated computational screening and experimental validation approach. Structure-based virtual screening of a bioactive natural product library derived from Traditional Chinese Medicine, combined with a novel consensus-ranking strategy, enabled the identification of flavonoid scaffolds targeting neurotrophin-binding sites of Trk receptors. Among these, Bavachin demonstrated robust, dose-dependent activation of both Trk-A and Trk-B receptors, but not Trk-C, indicating receptor selectivity. Induced-fit docking and molecular dynamics simulations revealed stable binding of Bavachin within conserved and receptor-specific ligand-binding pockets, consistent with its dual agonist activity. Collectively, this study identifies Bavachin as a putative small-molecule neurotrophin mimetic and establishes an integrated computational and experimental framework for the discovery of dual Trk-A/Trk-B agonists for neurodegenerative disease therapeutics.
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BibTeX
@misc{patil2026discovery,
title = {{Discovery of Bavachin as a Dual Trk-A/Trk-B Agonist via Integrated Computational Screening and Experimental Validation}},
author = {S. P. Patil and B. Kuehn and R. Schlosser and J. Samohod},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750759},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750759v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Discovery of Bavachin as a Dual Trk-A/Trk-B Agonist via Integrated Computational Screening and Experimental Validation
AU - S. P. Patil
AU - B. Kuehn
AU - R. Schlosser
AU - J. Samohod
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750759
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750759v1
AB - Neurotrophins regulate neuronal survival, differentiation, and synaptic plasticity through activation of tropomyosin receptor kinase (Trk) receptors, and their dysregulation is strongly implicated in neurodegenerative disorders, including Alzheimer's disease. However, the therapeutic application of recombinant neurotrophins remains limited by poor bioavailability, rapid degradation, and inadequate blood brain barrier permeability. Here, we report the discovery of Bavachin as a dual Trk-A/Trk-B neurotrophin mimetic via an integrated computational screening and experimental validation approach. Structure-based virtual screening of a bioactive natural product library derived from Traditional Chinese Medicine, combined with a novel consensus-ranking strategy, enabled the identification of flavonoid scaffolds targeting neurotrophin-binding sites of Trk receptors. Among these, Bavachin demonstrated robust, dose-dependent activation of both Trk-A and Trk-B receptors, but not Trk-C, indicating receptor selectivity. Induced-fit docking and molecular dynamics simulations revealed stable binding of Bavachin within conserved and receptor-specific ligand-binding pockets, consistent with its dual agonist activity. Collectively, this study identifies Bavachin as a putative small-molecule neurotrophin mimetic and establishes an integrated computational and experimental framework for the discovery of dual Trk-A/Trk-B agonists for neurodegenerative disease therapeutics.
ER -