Using a structure-guided approach to small molecule discovery and design, researchers have developed a drought-protective 'drug' for crops, according to a new study. The results show opabactin, the new synthetic abscisic acid (ABA) mimic, is nearly 10 times more effective than natural ABA in manipulating crop water use. Stomata, tiny pores scattered about the surface of a plant's leaves, open and close to regulate the exchange of both water vapor and carbon dioxide between the plant and the atmosphere. This mechanism, however, creates a tradeoff between plant growth and water use; improvements in one often come at the cost of the other. Therefore, developing crops that have improvements in both yield and water use efficiency has posed a significant agricultural challenge. Agrochemical 'drugs,' particularly those that mimic ABA - a hormone central to a plant's response to water availability - could potentially be used to sidestep this conundrum by enabling on-demand control of a plant's water use. As a result, ABA and its receptors have become an attractive target in both genetic and agrochemical approaches to improving drought tolerance in crops. Aditya Vaidya and colleagues found that the current synthetic ABA mimics demonstrate poor and short-lived bioactivity and are potentially limited by their weak affinity for necessary receptor targets. To address this, Vaidya et al. used virtual screening and structure-guided chemical design to discover and optimize the function of a more effective ABA agonist. The results show that their molecule demonstrates high potency in both wheat and tomato plants and imbued long-lasting protection against the adverse effects of underwatering when applied. "The new work provides important evidence that this chemical genomic approach may provide exciting new approaches to using chemicals, together with genetics, to create better water use efficiency in our most important crops," write George Phillips and Michael Sussman in a related Perspective.