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

Effects of β-hydroxybutyrate treatment on glycogen repletion and its related signaling cascades in epitrochlearis muscle during 120 min of postexercise recovery

We investigated the effects of β-hydroxybutyrate (β-HB), the most abundant type of ketone body in mammals, on postexercise glycogen recovery in skeletal muscle by using an in vitro experimental model. Male ICR mice swam for 60 min and then their epitrochlearis muscles were removed and incubated with either physiological levels of glucose (8 mmol/L) and insulin (60 μU/mL) or glucose and insulin plus 1, 2, or 4 mmol/L of sodium β-HB. Four millimoles per liter β-HB had a significant positive effect on glycogen repletion in epitrochlearis muscle at 120 min after exercise (p < 0.01), while 2 mmol/L of β-HB showed a tendency to increase the glycogen level (p < 0.09), and 1 mmol/L of β-HB had no significant effect. We further investigated the effect of 4 mmol/L β-HB treatment on the signaling cascade related to glycogen repletion in the epitrochlearis muscles throughout a 120-min recovery period. After incubating the muscles in 4 mmol/L of β-HB for 15 min postexercise, the Akt substrate of 160 kDa Thr642 (p < 0.05) and Akt Thr308 (p < 0.05) phosphorylations were significantly increased compared with the control treatment. At the same time point, 5′-AMP–activated protein kinase and acetyl-coenzyme A carboxylase phosphorylations were significantly lower (p < 0.05) in the epitrochlearis muscle incubated with 4 mmol/L of β-HB than in the control muscle. Our results demonstrate that postexercise 4 mmol/L β-HB administration enhanced glycogen repletion in epitrochlearis muscle. Four millimoles per liter β-HB treatment was associated with alternation of the phosphorylated status of several proteins involved in glucose uptake and metabolic/energy homeostasis at the early stage of postexercise.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Effects of combination of concentrated Kurozu supplementation and endurance training on mitochondrial enzyme activity and energy metabolism in mice

We examined the effects of endurance training with chronic pre-exercise concentrated Kurozu (black vinegar) supplementation on mitochondrial enzyme activity and energy metabolism in Institute of Cancer Research (ICR) mice. Mice were divided into a control group, an endurance training group, and an endurance training + concentrated Kurozu supplementation group. Mice were orally supplemented with water or concentrated Kurozu solution (500 mg/kg body weight/day) for 3 weeks. The mice in the training group were subjected to exercise on a treadmill (20–25 m/min × 30 min, five times/week) starting 30 min after the supplementation. The maximal activity of citrate synthase in the plantaris muscle in the endurance training + concentrated Kurozu supplementation group was significantly higher than that in the control group (p &lt; 0.01). The maximal activity of β-hydroxyacyl coenzyme dehydrogenase (β-HAD) in the soleus muscle in the endurance training + concentrated Kurozu supplementation group was significantly higher than that in the other two groups (p &lt; 0.05 for both). In the final week, significant negative correlation between blood lactate concentration after exercise and soleus β-HAD activity was observed. These findings suggest that endurance training with concentrated Kurozu supplementation increases mitochondrial enzyme activity and might enhance lipid metabolism during exercise