New ways to counter inflammation

Plant based medicines have been used throughout history and all over the planet to battle all varieties of ailments. Natural products often interact with the animal organism and show a wide array of health benefits while generally causing fewer harmful side effects than most synthetic drugs. While there are a lot of plant based medicines already in use, there is still a lot to learn about key active compounds and their mechanism of action. While synthetic drugs mainly focus on specifically interacting with a single protein target, natural products often interact with the organism via a poly-pharmacological mechanism, interacting with multiple proteins at once. This makes it especially challenging to elucidate their mechanism of action. This project aims to find novel anti-inflammatory natural products with the aid of computational methods. We create computational models of the interaction patterns between small molecule ligands and protein targets involved in inflammation (cyclooxygenase-1 and - 2, 5- and 15-lipoxygenase, 5-lipoxygenase-activating protein, soluble epoxides hydrolase, microsomal prostaglandin E2 synthase 1, and leukotriene C4 synthase). These models can then be used to computationally screen large compound databases to search for molecules that display a similar interaction pattern and consequently have a high likelihood of interacting with the protein in the biological experiment. We will create a set of such computational models, focusing on the structural properties of natural products and validate their predictive ability by biologically testing the virtual hits. Ultimately the validated models will be used in search of natural products that target multiple proteins. These poly pharmacologically active compounds are expected to have a high efficacy in vivo and to display a highly favorable side effect profile. By this process, we aim to identify not only active ingredients in plant based medicines but also novel anti- inflammatory compounds from natural sources, especially from food plants.

The project "New ways to counter inflammation" used computer models to search for natural products that interact with various proteins involved in inflammatory processes. Natural products, secondary plant metabolites, often bind to several target proteins, which makes them less selective on the one hand but also less prone to cause side effects. In the course of the project, both the structures of these natural products with multi target activity and the structures of their binding pockets were investigated for similarities. By creating and comparing simplified 3-dimensional computer models that represent the points of interaction between small molecules and the binding pockets of proteins (pharmacophore models), it is possible to define structural conditions that enable binding to several proteins simultaneously. As a result, activities for molecules can be predicted computationally, derived from their 2D structure. In the course of the project, a variety of such models were created and numerous new activities for natural products were discovered. For example, it was found that numerous natural inhibitors of the enzyme 5-lipoxygenase can also act as activators of 15-lipoxygenase and thus contribute to the resolution of inflammation. Furthermore, the benzylated dihydrochalcone MF-15 and its derivatives were investigated, which are able to inhibit the growth of otherwise resistant cancer cell lines selectively.