Novel and Effective Agrochemicals Derived From the Analysis of Molecular Fields

Non Technical Summary: Current estimates indicate that one-third of worldwide agricultural output is lost to pests and diseases such as pathogenic fungi. Despite advancements in chemical control, the rapid onset of resistance to pesticides often limits their utility. In addition, the vast majority of pesticide research projects are terminated before commercialization because of unattractive attributes of the lead chemical series, such as toxicity or high cost of manufacturing, which cannot be engineered out of the molecule. It is therefore desirable to identify alternate chemical scaffolds that retain efficacy against the pathogen by the desired mode of action while improving other characteristics. Divergence has successfully employed this `lead-hopping' strategy by acquiring a breakthrough technology that allows rapid and accurate comparisons of compounds based on crucial similarities in shape and electrostatics at the molecular surface, where target interactions occur. Divergence's expertise in agrochemical discovery and assay systems coupled with this fundamental advance in cheminformatics has allowed the creation of HarvestTM, a powerful platform for novel agrochemical discovery. Harvest has already resulted in the development of promising nematicides, and two pilot projects modeling fungicides have identified compounds effective against pathogenic fungi both in vitro and in greenhouse assays. Several hits from one screen also inhibit the intended molecular target in biochemical assays, providing further validation to this approach. Based on these data, we are expanding this platform to broad-spectrum and potent fungicide candidates that were never commercialized (e.g., because of prohibitive manufacturing costs). Candidates are prioritized when they possess a novel mode of action, which is highly valuable for control of fungicide resistance within integrated pest management programs. Based on a computational search of over four million structures for one lead candidate, Divergence will acquire ~300 molecules that (1) best match the cheminformatic model and (2) harbor properties indicative of successful agrochemicals. These compounds will be evaluated in the laboratory for activity against two fungal pathogens as well as biochemical inhibition of the target enzyme. Hits will be progressed into greenhouse studies. It is anticipated that 3-5 lead candidates will result from these screens, facilitating further model refinements and the acquisition/synthesis of more efficacious analogs for each scaffold. During Phase II, leads will progress into spectrum testing against additional fungal species and preliminary toxicology testing before the prioritization of one lead series for analog synthesis and eventual progression into field trials. A safe and efficacious fungicide with a novel mode of action will be highly beneficial to commercial partners, agricultural producers, consumers, and the environment.