Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on transformer model.

Abstract

Succinate dehydrogenase (SDH), also termed complex II or succinate-ubiquinone oxidoreductase, is a crucial biological enzyme in the process of mitochondrial oxidative phosphorylation. Succinate dehydrogenase inhibitors (SDHIs) are a promising class of fungicides targeting the energy production pathway of pathogenic fungi. However, overuse has resulted in the emergence of resistance, underscoring the need for novel and effective SDHIs. This study utilized the Transformer model to generate a customized virtual library of potential SDHIs. These candidates were then meticulously screened based on expert knowledge and synthetic feasibility, ultimately yielding several pyrazole carboxamide derivatives as the promising leads. Subsequent synthesis, antifungal activity assessment, and structural optimization further refined these leads into potent SDHI candidates. This work represents the first application of a generative model to SDHI design, establishing a robust workflow encompassing virtual library generation, screening, activity evaluation, and structure optimization. This study paves the way for the rational design of future SDHIs, not only against fungi, but potentially other agricultural pathogens as well.