Defining the limits of plant chemical space: challenges and estimations

The plant kingdom, encompassing nearly 400,000 known species, produces an immense diversity of metabolites, including primary compounds essential for survival and secondary metabolites specialized for ecological interactions. These metabolites constitute a vast and complex phytochemical space with significant potential applications in medicine, agriculture, and biotechnology. However, much of this chemical diversity remains unexplored, as only a fraction of plant species has been studied comprehensively. In this work, we estimate the size of the plant chemical space by leveraging large-scale metabolomics and literature datasets. We begin by examining the known chemical space, which, while containing at most several hundred thousand unique compounds, remains sparsely covered. Using data from over 1,000 plant species, we apply various mass spectrometry-based approaches-a formula prediction model, a de novo prediction model, a combination of library search and de novo prediction, and MS2 clustering-to estimate the number of unique structures. Our methods suggest that the number of unique compounds in the metabolomics dataset alone may already surpass existing estimates of plant chemical diversity. Finally, we project these findings across the entire plant kingdom, estimating that the total plant chemical space likely spans millions, if not more, with most still unexplored.