Author
Sreshtha Malik
sreshtha.malik@adelaide.edu.au
University of Adelaide
Adelaide
Coauthors
Andrew Barrow, University Of Adelaide, Adelaide, Australia
Tatiana Soares da Costa, University Of Adelaide, Adelaide, Australia
Abstract
The rise in herbicide-resistant weeds, combined with the lack of new herbicides over the past four decades, highlights the urgent need to identify herbicides with novel targets. Traditional herbicide discovery approaches are time-consuming, expensive, and have a low success rate. To address this, we developed a novel structure-based virtual screening pipeline tailored for herbicide discovery, designed to reduce the risk of downstream toxicity, and applied it to plant shikimate kinase (SK), a commercially untapped herbicide target. Screening millions of ZINC database compounds, our pipeline identified 18 hit candidates. In vitro assays confirmed 15 compounds as plant SK inhibitors, with five showing micromolar potency. Two leads exhibited potent pre-emergence herbicidal activity without off-target effects on soil microflora. Binding mode analysis indicated interactions with conserved substrate-binding residues. To our knowledge, this is the first report of plant SK inhibitors discovered via virtual screening with confirmed herbicidal activity. Beyond this proof-of-concept, our pipeline is broadly applicable to other compound libraries and molecular targets. In particular, it can be extended to prioritise naturally occurring scaffolds from fungi and bacteria by building focused libraries of microbe-derived compounds and screening them for herbicidal properties. This strategy offers an avenue to discover bio-inspired herbicides and, importantly, positions virtual screening as a complementary approach to classical biocontrol within integrated weed management. Collectively, this work reinforces SK as a promising herbicide target and establishes structure-based virtual screening as a versatile tool to accelerate the discovery of much-needed new herbicides.
keywords
virtual screening
herbicide discovery
shikimate kinase
bio-inspired herbicides
microbe-derived scaffolds
structure-based design
toxicity de-risking
integrated weed management
Highlights
Structure-based virtual screening pipeline identifies shikimate kinase inhibitors with confirmed pre-emergence herbicidal activity.
Workflow designed to de-risk downstream toxicity and is readily extensible to microbe-derived (bio-inspired) scaffolds.
Positions virtual screening as a complementary approach to classical biocontrol within integrated weed management.