Cheminformatics and artificial intelligence for accelerating agrochemical discovery.

The global cost-benefit analysis of pesticide use during the last 30 years has been characterized by a significant increase during the period from 1990 to 2007 followed by a decline. This observation can be attributed to several factors including, but not limited to, pest resistance, lack of novelty with respect to modes of action or classes of chemistry, and regulatory action. Due to current and projected increases of the global population, it is evident that the demand for food, and consequently, the usage of pesticides to improve yields will increase. Addressing these challenges and needs while promoting new crop protection agents through an increasingly stringent regulatory landscape requires the development and integration of infrastructures for innovative, cost- and time-effective discovery and development of novel and sustainable molecules. Significant advances in artificial intelligence (AI) and cheminformatics over the last two decades have improved the decision-making power of research scientists in the discovery of bioactive molecules. AI- and cheminformatics-driven molecule discovery offers the opportunity of moving experiments from the greenhouse to a virtual environment where thousands to billions of molecules can be investigated at a rapid pace, providing unbiased hypothesis for lead generation, optimization, and effective suggestions for compound synthesis and testing. To date, this is illustrated to a far lesser extent in the publicly available agrochemical research literature compared to drug discovery. In this review, we provide an overview of the crop protection discovery pipeline and how traditional, cheminformatics, and AI technologies can help to address the needs and challenges of agrochemical discovery towards rapidly developing novel and more sustainable products.

C5 methylation confers accessibility, stability and selectivity to picrotoxinin.

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

A Computational Investigation of the Ligand-Controlled Cu-Catalyzed Site-Selective Propargylation and Allenylation of Carbonyl Compounds.

A copper-catalyzed site-selective propargylation/allenylation reaction toward carbonyl compounds has been mechanistically investigated using a computational approach. Different reaction pathways and catalytic cycles were investigated. Control of the site selectivity arises from a destabilizing interaction introduced by the phenyl-substituted ligand.

GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism.

Ocular albinism type 1 (OA), caused by mutations in the OA1 gene, encodes a G-protein coupled receptor, OA1, localized in melanosomal membranes of the retinal pigment epithelium (RPE). This disorder is characterized by both RPE macro-melanosomes and abnormal decussation of ganglion cell axons at the brain's optic chiasm. We demonstrated previously that Oa1 specifically activates Gαi3, which also signals in the Oa1 transduction pathway that regulates melanosomal biogenesis. In this study, we screened the human Gαi3 gene, GNAI3, in DNA samples from 26 patients who had all clinical characteristics of OA but in whom a specific mutation in the OA1 gene had not been found, and in 6 normal control individuals. Using the Agilent HaloPlex Target Enrichment System and next-generation sequencing (NGS) on the Illumina MiSeq platform, we identified 518 variants after rigorous filtering. Many of these variants were corroborated by Sanger sequencing. Overall, 98.8% coverage of the GNAI3 gene was obtained by the HaloPlex amplicons. Of all variants, 6 non-synonymous and 3 synonymous were in exons, 41 in a non-coding exon embedded in the 3' untranslated region (UTR), 6 in the 5' UTR, and 462 in introns. These variants included novel SNVs, insertions, deletions, and a frameshift mutation. All were found in at least one patient but none in control samples. Using computational methods, we modeled the GNAI3 protein and its non-synonymous exonic mutations and determined that several of these may be the cause of disease in the patients studied. Thus, we have identified GNAI3 as a second gene possibly responsible for X-linked ocular albinism.