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

Microdroplet sandwich real-time rt-PCR for detection of pandemic and seasonal influenza subtypes.

As demonstrated by the recent 2012/2013 flu epidemic, the continual emergence of new viral strains highlights the need for accurate medical diagnostics in multiple community settings. If rapid, robust, and sensitive diagnostics for influenza subtyping were available, it would help identify epidemics, facilitate appropriate antiviral usage, decrease inappropriate antibiotic usage, and eliminate the extra cost of unnecessary laboratory testing and treatment. Here, we describe a droplet sandwich platform that can detect influenza subtypes using real-time reverse-transcription polymerase chain reaction (rtRT-PCR). Using clinical samples collected during the 2010/11 season, we effectively differentiate between H1N1p (swine pandemic), H1N1s (seasonal), and H3N2 with an overall assay sensitivity was 96%, with 100% specificity for each subtype. Additionally, we demonstrate the ability to detect viral loads as low as 10(4) copies/mL, which is two orders of magnitude lower than viral loads in typical infected patients. This platform performs diagnostics in a miniaturized format without sacrificing any sensitivity, and can thus be easily developed into devices which are ideal for small clinics and pharmacies

Primer sets and sensitivities for each subtype.

<p>Primer sets and sensitivities for each subtype.</p

Serial dilution of H3 vRNA of 10⁹−10⁵ copies/mL.

<p>Threshold was calculated as 10× standard deviation of the background signal. 10⁵ copies/mL was the lowest concentration amplified using the one-step RT-PCR reaction on the tablet platform. Legend: 10⁹ copies/mL (pink▾), 10⁸ copies/mL (red •), 10⁷ copies/mL (green▴), 10⁶ copies/mL (blue▾), 10⁵ copies/mL (turquoise ♦), threshold (black ▪). Inset: Efficiency plot of H3 vRNA serial dilution series. Displays the Ct values vs. log concentration of vRNA, with a linear regression fit of R² = 0.998. The slope of the line is −3.38, providing an efficiency of 97.6% using E = 10^(−1/slope)−1 with an average standard deviation of ±1.3 cycles.</p

Droplet sandwich platform.

<p>a: Drawings of platform: 3D drawing of the droplet sandwich platform displaying the ITO coated glass (a) with a compound droplet (b) surrounded by a spacer (c) and covered with a coverslip (d), which is fully assembled to sandwich the compound droplet in a reaction chamber (e). The ITO surface heats radially, as displayed the modeled heating profile for the ITO glass when 15 V is applied to the resistive surface as generated by COMSOL Multiphysics (f). The dimension of the slide is 40 mm×40 mm and the compound droplet is approximately 2.8 mm in diameter. b: Workflow and representative data: Sample isolation is done from nasopharygeal swabs and the rtRT-PCR mix is transferred to the droplet sandwich platform for thermal cycling. Temperature cycling occurs at the center of the radial profile as displayed by the plot where the black line represents the controlled surface temperature and the red line is the calibrated droplet temperature. Fluorescence is collected in real-time during the extension phase of PCR, with DNA amplification of positive samples displayed in green, negative samples with no change over time in blue and calculated threshold in black.</p

Supplementary Figure S5 from Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX

Supplementary Figure S5</p

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer.

Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in&nbsp;vitro, cell-line and patient-derived xenografts in&nbsp;vivo, and ex&nbsp;vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in&nbsp;vitro and in&nbsp;vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens

Supplementary Figure S6 from Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX

Supplementary Figure S6</p

Supplementary Figure S1 from Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX

Supplementary Figure S1</p