Exploring evolutionary and chemical space using chemoinformatic tools and traditional methods in pharmacognosy

Abstract: The number of new drugs coming to the market is declining while interest in lead discovery from natural resources is seeing a revival. Although methods for isolation and identification of natural products have advanced tremendously, methods for selection of potential leads have fallen behind. As part of the Marie Curie ITN “MedPlant: Phylogenetic exploration of medicinal plant diversity” this thesis contributed to the exploration of chemical diversity in angiosperms and the development of new tools to analyze and define the chemical potential of a plant.In Paper I, it was demonstrated that physicochemical properties of selected specialized metabolites change in different plant groups. Changes in properties were assessed using ChemGPS-NP and diversity was quantified by calculating the volume occupied by the compounds in chemical space. By discussing the results against the background of possible underlying evolutionary mechanisms, it was concluded that evolutionary processes are reflected in chemical property space. These results hold great value for further studies on the evolution of chemical diversity and biochemical traits in plants. The methods developed can be used e.g. to define and predict the chemical diversity of related taxa, providing a strategy for a guided plant selection in search for new drug leads.In Paper II, the scaffold and molecular diversity of over 5,200 sesquiterpene lactones (STLs) was investigated, using different chemoinformatic tools. Quantity and distribution of skeleton classes was determined and it was shown that different plant families possess specific sets of molecular frameworks, with considerable variation in their frequency. Clustering analysis enabled qualitative division of STLs into smaller groups with similar structural features, pointing out the differentiation of various plant groups. Including the study results, the dataset offers a compelling resource for chemosystematics, natural product research and drug lead discovery focused on STLs. It provides the basis for phylogenetic implementations due to the detailed taxonomic annotation. Since STLs display a source for new drugs, it is of high value for a guided search for plant derived drug leads.In Paper III, Lindera benzoin was subjected to phytochemical and pharmacological investigations. Phytochemical investigations led to the isolation of three new sesquiterpenes. As Native American tribes used this shrub for various medicinal purposes, e.g. cold remedy or diaphoretic, the isolated compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, they reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner, which may rationalize the traditional use of this plant.