Protoporphyrinogen oxidase inhibitors discovered by Artificial Intelligence platform

Abstract

Background: Weed control is essential in modern agriculture, though it has become more difficult with the emergence of resistance to most current herbicides and the slow registration process for new compounds. Objective: Identify herbicide candidates using an innovative artificial intelligence algorithm that takes into effect biological parameters with the goal of reducing research and development time of new herbicides. Results: We describe the discovery of 4-chloro-2-pentenamides as novel inhibitors of protoporphyrinogen oxidase (PPO), a known herbicide target site, by the Agrematch AI. Their herbicidal activity was evaluated in greenhouse assays, with the highest performing compound (AGR001) showing good activity pre-emergent at 150 g ha-1 and post emergent at 50 g ha-1 on the troublesome weed Palmer amaranth (Amaranthus palmeri). A lack of activity is reported on PPO resistant Palmer amaranth carrying the glycine 210 deletion (ΔG210) mutation. Conclusions: The mode of action of 4-chloro-2-pentenamides was confirmed by the herbicide-dependent accumulation of protoporphyrin IX, subsequent light-dependent loss of membrane integrity, and direct in vitro inhibition of PPO. Modeling of these inhibitors’ docking in the active site of PPO shows that their flexible side chains can accommodate several binding poses in the catalytic domain.