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Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores. 

The lack of suitable tools for the identification of potential drug leads from complex matrices is a bottleneck in drug discovery. Here, we report a novel method to screen complex matrices for new drug leads targeting transmembrane receptors. Using α 3 β 4 nicotinic receptors as a model system, we successfully demonstrated the ability of this new tool for the specific identification and effective extraction of binding compounds from complex mixtures. The formation of cell-membrane coated nanoparticles was confirmed by transmission electron microscopy. In particular, we have developed a direct tool to evaluate the presence of functional α 3 β 4 nicotinic receptors on the cell membrane. The specific ligand binding to α 3 β 4 nicotinic receptors was examined through ligand fishing experiments and confirmed by high-performance liquid chromatography coupled with diode-array detection and electrospray ionization mass spectrometry. This tool has a great potential to transform the drug discovery process focusing on identification of compounds targeting transmembrane proteins, as more than 50% of all modern pharmaceuticals use membrane proteins as prime targets.