Discovering new mode‐of‐action pesticide leads inhibiting protein–protein interactions: example targeting plant O‐acetylserine sulfhydrylase

Abstract

BACKGROUNDThe widespread evolution of pesticide resistance poses a significant challenge to current agriculture, necessitating the discovery of molecules with new modes of action. Despite extensive efforts, no major molecules with new modes of action have been commercialized for decades. Most pesticides function by binding to specific pockets on target enzymes, enabling a single target site mutation to confer resistance. An alternative approach is the disruption of protein–protein interactions (PPI), which require complementary mutations on both interacting partners for resistance to occur. Thus, our aim is the discovery and design of small‐molecule inhibitors that target the interface of the PPI complex of O‐acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key obligatory interacting plant enzymes involved in the biosynthesis of the amino acid cysteine.RESULTSBy employing in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT with a half‐maximal inhibitory concentration (IC50) of 34 μm. Subsequently, we conducted molecular chemical optimizations, generating an early lead molecule (PJ4) with an IC50 value of 4 μm. PJ4 successfully inhibited the germination of Arabidopsis thaliana seedlings and inhibited clover growth in a pre‐emergence application at an effective concentration of 4.6 kg ha−1.CONCLUSIONThese new compounds described herein can serve as promising leads for further optimization as herbicides with a new mode‐of‐action. This technology can be used for discovering new modes of action chemicals inhibiting all pest groups. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.