Discovery and design of small-molecule inhibitors

The heavy use of herbicides, applies constant selection pressure on weeds and resistance. Thus, there is an urgent need for the development of herbicides with new mode of action. Important factor in considering new herbicides is that these molecules should only target plants and not animals. Small molecules targeting enzymes participating in amino acids synthesis have the potential to demonstrate herbicidal activity. Among the essential amino acids, the biosynthesis pathway of methionine was less utilized for the development of inhibitors in comparison to other amino acid synthesis pathways. Methionine is not only used as a building block in plant proteins, but also serves as the first codon-initiating mRNA translation. Methionine`s main catabolic product - S-adenosylmethionine (SAM), regulates variety of cellular processes such as, synthesis of the plant hormone, ethylene, vitamins such as biotin, and of the polyamines spermidine and spermine, playing crucial roles in many aspects of plant growth, including cell proliferation and differentiation, apoptosis, homeostasis and gene expression. The first unique enzyme of the methionine pathway, cystathionine gamma-synthase (CgS) is the key regulatory enzyme of this pathway and thus can serve as a good target for potential new herbicides. Using computational, biophysical and biochemical tools we screened a library of small molecules to find potential inhibitors CgS. Successful candidates were examined and validated for their ability to bind and inhibit CgS in-vitro and in-planta. These compounds may be further developed as new herbicides in a new mode of action.