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

Biosimilars: what clinicians should know.

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators

Climate anomalies and neighbourhood crowding interact in shaping tree growth in old‐growth and selectively logged tropical forests

International audienceClimate extremes and biotic interactions at the neighbourhood scale affect tropical forest dynamics with long‐term consequences for biodiversity, global carbon cycling and climate change mitigation. However, forest disturbance may change crowding intensity, and thus the relative contribution of climate extremes and neighbourhood interactions on tree growth, thereby influencing tropical forest resistance and resilience to climate change. Here, we aim to evaluate the separate and interactive effects of climate and neighbours on tree growth in old‐growth and disturbed tropical forests. We used 30 years of growth measurements for over 300 tropical tree species from 15 forest plots in French Guiana to investigate the separate and interactive effects of climate anomalies (in solar radiation, maximum temperature, vapour pressure deficit and climatic water deficit) and neighbourhood crowding on individual tree growth. Contrasting old‐growth and selectively logged forests, we also examined how disturbance history affects tree growth sensitivity to climate and neighbours. Finally, for the most abundant 100 species, we evaluated the role of 12 functional traits pertaining to water relations, light and carbon use in mediating tree growth sensitivity to climate anomalies, neighbourhood crowding and their interactions. Climate anomalies tied to heat and drought stress and neighbourhood crowding independently reduced tree growth, and showed positive interactive effects which attenuated their separate effects on tree growth. Their separate and interactive effects were stronger in disturbed than undisturbed forests. Fast‐growing species (i.e. higher intrinsic growth rates) were more abundant in disturbed forests and more sensitive to climate anomalies and neighbourhood crowding. Traits related to water relations, light and carbon use captured species sensitivities to different climate anomalies and neighbourhood crowding levels but were weak predictors of their interactions. Synthesis : Our results demonstrate that climate anomalies and neighbourhood crowding can interact to shape tropical tree growth, suggesting that considering the biotic context may improve predictions of tropical forest dynamics facing altered climate regimes. Furthermore, species traits can capture tree growth sensitivity to the separate effects of climate and neighbours, suggesting that better representing leading functional dimensions in tropical tree strategies offers a promising way towards a better understanding of the underlying ecological mechanisms that govern tropical forest dynamics.Les extrêmes climatiques ainsi que les interactions biotiques à l'échelle du voisinage, affectent la dynamique des forêts tropicales, avec des conséquences à long terme pour la biodiversité, le cycle global du carbone et l'atténuation du changement climatique. Cependant, les perturbations forestières peuvent faire varier localement les voisinages, et ainsi modifier la contribution relative des extrêmes climatiques et des interactions de voisinage sur la croissance des arbres, ce qui peut impacter la résistance et la résilience des forêts tropicales au changement climatique. Nos travaux visent à évaluer les effets individuels et interactifs du climat et des voisins sur la croissance des arbres dans les forêts tropicales non‐pertubées et perturbées. Nous avons utilisé 30 ans de mesures de croissance pour plus de 300 espèces d'arbres tropicaux provenant de 15 parcelles forestières en Guyane française pour étudier les effets individuels et interactifs des anomalies climatiques (en termes de rayonnement solaire, de température maximale, de déficit de pression de vapeur, et de déficit hydrique climatique) et des interactions de voisinage sur la croissance individuelle des arbres. En comparant les forêts exploitées sélectivement aux forêtsnon‐pertubées, nous avons également examiné comment l'historique des perturbations peut influencer la sensibilité de la croissance des arbres au climat et aux voisins. Enfin, pour les 100 espèces les plus abondantes, nous avons évalué le rôle de 12 traits fonctionnels reflétant les relations hydriques, l'utilisation de la lumière et du carbone sur la réponse de la croissance des arbres aux anomalies climatiques, aux interactions de voisinage et à leurs interactions. Les anomalies climatiques liées aux stress thermique et hydrique, ainsi que les interactions de voisinage, réduisent la croissance des arbres. De plus, elles peuvent interagir positivement, ce qui atténue leurs effets individuels sur la croissance des arbres. Leurs effets individuels et interactifs sont plus forts dans les forêts perturbées que dans les forêts non‐perturbées. Les espèces à croissance rapide (c'est‐à‐dire à taux de croissance intrinsèque plus élevé) sont plus abondantes dans les forêts perturbées, et aussi plus sensibles aux anomalies climatiques et aux interactions de voisinage. Les traits liées aux relations hydriques, à la lumière et à l'utilisation du carbone captent la sensibilité des espèces aux différentes anomalies climatiques et aux différents niveaux d'interactions de voisinage, mais ne prédisent pas leurs interactions. Synthèse : Nos résultats montrent que les anomalies climatiques et les interactions de voisinage peuvent interagir pour façonner la croissance des arbres tropicaux, ce qui suggère que prendre en compte le contexte biotique peut améliorer les prévisions de la dynamique des forêts tropicales face aux changements climatiques. En outre, les traits des espèces peuvent capter la sensibilité de la croissance des arbres aux effets individuels du climat et des voisins, ce qui suggère que mieux représenter les principales dimensions des stratégies fonctionnelles des arbres tropicaux ouvre sur une meilleure compréhension des mécanismes écologiques qui régissent la dynamique des forêts tropicales