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

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

General Synthesis of Unsymmetrical 3,3′-(Aza)diindolylmethane Derivatives

Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to their significant biological activities, specifically in cancer prevention and therapy. Molecular targets of DIM have been identified, e.g., the immunostimulatory G protein-coupled receptor GPR84. However, most of the reported and investigated DIM derivatives are symmetrical because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required. In the present study we developed a new, mild and efficient access to unsymmetrically substituted 3,3′-DIMs by reaction of (3-indolylmethyl)­trimethylammonium iodides with a wide range of substituted indole derivatives. 7-Azaindole also led to the 3,3′-connected DIM analogue, while 4- and 5-azaindoles reacted at the <i>N</i>1-nitrogen atom as confirmed by X-ray crystallography. The reactions were performed in water without the requirement of a catalyst or other additives. Wide substrate scope, operational simplicity, environmentally benign workup, and high yields are further advantages of the new method. The synthetic protocol proved to be suitable for upscaling to yield gram amounts for pharmacological studies. This procedure will allow the preparation of a broad range of novel, unsymmetrical DIM derivatives to exploit their potential as novel drugs

6‑Bromo-8-(4‑[³H]methoxybenzamido)-4-oxo‑4<i>H</i>‑chromene-2-carboxylic Acid: A Powerful Tool for Studying Orphan G Protein-Coupled Receptor GPR35

The potent and selective GPR35 agonist 6-bromo-8-(4-methoxybenzamido)-4-oxo-4<i>H</i>-chromene-2-carboxylic acid (<b>12</b>) was obtained in tritium-labeled form, designated [³H]­PSB-13253, with a specific activity of 36 Ci (1.33 TBq)/mmol. Radiolabeling was achieved by methylation of ethyl 6-bromo-8-(4-((<i>tert</i>-butyldimethylsilyl)­oxy)­benzamido)-4-oxo-4<i>H</i>-chromene-2-carboxylate (<b>19</b>) with [³H]­methyl tosylate followed by ester hydrolysis. The radioligand was characterized by kinetic, saturation, and competition assays at membrane preparations of Chinese hamster ovary cells recombinantly expressing the human GPR35. [³H]<b>12</b> labeled the receptor with high affinity (<i>K</i>_D = 5.27 nM). Binding was saturable (<i>B</i>_max = 12.6 pmol/mg of protein) and reversible. Affinities of selected standard ligands and a library of amidochromen-4-one-2-carboxylates were determined. Binding data mostly correlated with potencies determined in β-arrestin assays. On the basis of the test results, several new fluorine-substituted 6-bromo-8-benzamidochromen-4-one-2-carboxylic acids were obtained, which represent the most potent GPR35 agonists known to date. 6-Bromo-8-(2,6-difluoro-4-methoxybenzamido)-4-oxo-4<i>H</i>-chromene-2-carboxylic acid (<b>83</b>; <i>K</i>_i = 0.589 nM, EC₅₀ = 5.54 nM) showed the highest affinity with a <i>K</i>_i value in the subnanomolar range

Convergence : mensuel de la solidarité / Secours populaire français ; dir. publ. Julien Lauprêtre ; réd. Antonio Garcia, Valmont Ponceau

mars 19861986/03 (N49)-1986/03.Appartient à l’ensemble documentaire : UnivJeun

Indazole- and Indole-5-carboxamides: Selective and Reversible Monoamine Oxidase B Inhibitors with Subnanomolar Potency

Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were <i>N</i>-(3,4-dichlorophenyl)-1-methyl-1<i>H</i>-indazole-5-carboxamide (<b>38a</b>, PSB-1491, IC₅₀ human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and <i>N</i>-(3,4-dichlorophenyl)-1<i>H</i>-indole-5-carboxamide (<b>53</b>, PSB-1410, IC₅₀ human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (<i>E</i>)-<i>N</i>-(3,4-dichlorophenyl)-1-(1<i>H</i>-indazol-5-yl)­methanimine (<b>58</b>) represents a further novel class of highly potent and selective MAO-B inhibitors (IC₅₀ human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In <i>N</i>-(3,4-difluorophenyl-1<i>H</i>-indazole-5-carboxamide (<b>30</b>, PSB-1434, IC₅₀ human MAO-B 1.59 nM, selectivity versus MAO-A >6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors’ interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size

Antagonists for the Orphan G‑Protein-Coupled Receptor GPR55 Based on a Coumarin Scaffold

The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson’s disease, neuropathic pain, and cancer. We applied β-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure–activity relationship study for GPR55. Selectivity versus the related receptors CB₁, CB₂, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2<i>H</i>-chromen-2-one (<b>12</b>, PSB-SB-489, IC₅₀ = 1.77 μM, p<i>A</i>₂ = 0.547 μM). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2<i>H</i>-chromen-2-one (<b>69</b>, PSB-SB-487, IC₅₀ = 0.113 μM, <i>K</i>_B = 0.561 μM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2<i>H</i>-chromen-2-one (<b>67</b>, PSB-SB-1203, IC₅₀ = 0.261 μM) were the most potent GPR55 antagonists of the present series

Development of [³H]2-Carboxy-4,6-dichloro‑1<i>H</i>‑indole-3-propionic Acid ([³H]PSB-12150): A Useful Tool for Studying GPR17

The recently described synthetic GPR17 agonist 2-carboxy-4,6-dichloro-1<i>H</i>-indole-3-propionic acid (<b>1</b>) was prepared in tritium-labeled form by catalytic hydrogenation of the corresponding propenoic acid derivative <b>8</b> with tritium gas. The radioligand [³H]­PSB-12150 (<b>9</b>) was obtained with a specific activity of 17 Ci/mmol (629 GBq/mmol). It showed specific and saturable binding to a single binding site in membrane preparations from Chinese hamster ovary cells recombinantly expressing the human GPR17. A competition assay procedure was established, which allows the determination of ligand binding affinities

Virtual Screening Identifies Novel Sulfonamide Inhibitors of <i>ecto</i>-5′-Nucleotidase

We aimed to identify inhibitors of <i>ecto</i>-5′-nucleotidase (<i>ecto</i>-5′-NT, CD73), a membrane-bound metallophosphoesterase that is implicated in the control of purinergic receptor signaling and a number of associated therapeutically relevant effects. Currently, only very few compounds, including ADP, its more stable analogue α,β-methylene-ADP, ATP, and anthraquinone derivatives are known to inhibit this enzyme. In the search for inhibitors with more drug-like properties, we applied a model structure-based virtual screening approach augmented by chemical similarity searching. On the basis of this analysis, 51 candidate compounds were finally selected for experimental evaluation. A total of 13 of these molecules were confirmed to have competitive inhibitory activity. The most potent inhibitor, 6-chloro-2-oxo-<i>N</i>-(4-sulfamoylphenyl)-2<i>H</i>-chromene-3-carboxylic acid amide (<b>17</b>), showed an IC₅₀ value of 1.90 μM. In contrast to the nucleotide- and anthraquinone-derived antagonists, the newly identified competitive inhibitors are uncharged at physiological pH values, possess a drug-like structure, and are structurally distinct from known active compounds