AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The recording of floods and earthquakes in Lake Chichój, Guatemala during the twentieth century

International audienceLaguna Chicho'j (Lake Chicho' j) is the only deep permanent lake in the central highlands of Guatemala. The lake is located in the boundary zone between the North American and Caribbean plates. The lake has been struck by devastating earthquakes and tropical cyclones in historical times. We investigated the imprint of twentieth century extreme events on the sedimentary record of this tropical lake using a bathymetric survey of the lake, coring the lake floor, and providing a chronology of sediment accumulation. The lake occupies a series of circular depressions likely formed by the rapid dissolution of a buried body of gypsum. 210Pb and 137Cs inventories and varve counting indicate high rates of sedimentation (1-2 cm year-1). The annually layered sediment is interrupted by turbidites of two types: a darker-colored turbidite, enriched in lake-derived biogenic constituents, and interpreted as a seismite, and a lightercolored type, enriched in catchment-derived constituents, interpreted as a flood layer. Comparison of our 137Cs-determined layer ages with a catalog of twentieth century earthquakes shows that an earthquake on the Motagua fault in 1976 generated a conspicuous darker-colored turbidite and slumped deposits in separate parts of the lake. The entire earthquake inventory further reveals that mass movements in the lake are triggered at Modified Mercalli Intensities higher than V. Tropical cyclonic depressions known to have affected the lake area had limited effect on the lake, including Hurricane Mitch in 1998. One storm however produced a significantly thicker flood layer in the 1940s. This storm is reportedly the only event to have generated widespread slope failures in the lake catchment. It is thus inferred that abundant landsliding provided large amounts of concentrated sediment to the lake, through hyperpycnal flow