Short Lecture “From in silico to in vivo: Psychotria nemorosa alkaloids counter protein toxicity in Caenorhabditis elegans”

Usually, novel natural products are isolated in small amounts. This makes it difficult to explore their pharmacological targets in vitro and explore their effects in vivo. Hence, approaches to streamline these obstacles are pursued, two of which are addressed in this study: (1) In silico models to rationalize molecular target testing, (2) Caenorhabditis elegans as in vivo model to test compounds at the scale of an in vitro cellular assay.

We present a discovery pipeline for two azepine-indole alkaloids, nemorosine A (1) and fargesine (2), which have been identified as the main azepine-indole alkaloids of Psychotria nemorosa [1]. To explore their pharmacological profile, we applied an in silico molecular target fishing approach which is based on 3D similarity searches of the ChEMBL database [2]. Hereby, structurally related compounds that modulate the 5-HT2 receptor were identified. In vitro experiments confirmed an agonistic effect of 1 and 2 at the 5-HT2A receptor. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition [1], prompted the evaluation of these compounds in several C. elegans models linked to 5-HT signalling and proteotoxicity. Alkaloids 1 and 2 inhibited C. elegans motility and pharyngeal pumping. They alleviated amyloid beta proteotoxicity in transgenic strain CL4659 and reduced α-synuclein accumulation in transgenic strain NL5901.

These results add to the multi-target profiles of 1 and 2 and corroborate their potential in the treatment of neurodegeneration. They also highlight the capability of pipelines employing both in silico and nematode models [3].

 

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• References

• 1 Klein-Júnior LC, Cretton S, Vander Heyden Y. et al. Bioactive azepine-indole alkaloids from Psychotria nemorosa. J Nat Prod 2020; 83 (04) 852-863
• 2 Chen Y, Mathai N, Kirchmair J. Scope of 3D shape-based approaches in predicting the macromolecular targets of structurally complex small molecules including natural products and macrocyclic ligands. J Chem Inf Model 2020; 60 (06) 2858-2875
• 3 Kirchweger B, Klein-Júnior LC, Pretsch D. et al. Azepine-indole alkaloids from Psychotria nemorosa modulate 5-HT2A receptors and prevent in vivo protein toxicity in transgenic Caenorhabditis elegans. Front Neurosci 2022; 16: 826289

Publikationsverlauf

Artikel online veröffentlicht:
12. Dezember 2022