Periodic Reporting for period 1 - KavaTarget (Identification of molecular targets of psychoactive kavalactones using iBodies)
Reporting period: 2021-01-01 to 2022-12-31
Advances in genomics and metabolomics technologies have rekindled drug discovery efforts using natural chemicals. However, the identification of protein targets of these new bioactive molecules remains laborious. To address this issue, the KavaTarget project aimed to design a novel methodology for discovering molecular targets of small molecules using innovative probes called iBodies. The project focused on metabolites with well-documented anti-anxiety properties from Piper methysticum or kava, a crop of the Pacific islands. The project aimed to validate the approach by identifying the brain receptors and hepatocyte enzymes that constitute primary targets of these kava metabolites. Although the project deviated from its original course during the implementation, it has contributed significantly to the development of metabolomics technologies and mapped new interactions between human receptors and small bioactive molecules from plants.
Over the course of the project, a high-throughput screening method for vanilloid-mediated activation of the human pain receptor TRPV1 was developed and used to characterize new capsaicinoids and their synergistic effects on the receptor. The project contributed significantly to the development of new metabolomics technologies, particularly related to the MZmine platform for mass spectrometry data processing. The originally envisioned iBodies approach failed due to the complexity of the linker chemistry, preventing progress in identifying brain or liver targets of kavalactones. However, the project overall resulted in 15 research publications or preprints. The project also helped with establishing new international collaborations and new research directions emerged, particularly in the areas metabolomics and machine learning applications to biochemistry.
The project advanced our understanding of interactions between small molecules and human receptors, particularly for capsaicinoids derived from chili plants and their interactions with the human pain receptor TRPV1. On the technical level, the project helped deliver new methodologies and tools for computational metabolomics, particularly related to the MZmine project for mass spectrometry data processing.