Small molecule inhibitors of cystathionine gamma-synthase in plants for modulating methionine synthesis

Amino acid synthesis in plants and bacteria is essential for their survival and growth. In plants, such cellular processes are targeted in order to discover new herbicides for weed control. In our recent work, we describe the discovery and further optimization of inhibitors of cystathionine gamma-synthase, a key enzyme in the biosynthesis of methionine in plants and bacteria. Based on structural analysis to determine the key features required to display inhibition, followed by virtual screening of large database of small-molecules we identified potential compounds predicted to inhibit cystathionine gamma-synthase. We then tested a subset of the predicted hits in-vitro and verified their activity. We used the molecular structure of cystathionine gamma-synthase to generate a model of the protein-inhibitor complex based on which we rationally designed improved chemical analogues and characterized their activity. Indeed, successful analogues with validated in-vitro activity and binding, displayed efficient inhibition on BY-2 tobacco cells measuring viability and of seed germination of Arabidopsis thaliana in agar plates.