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

Alzheimer's associated inflammation, potential drug targets and future therapies

Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants

Hydrogen peroxide is a true first messenger

Hydrogen peroxide has been shown to act as a second messenger mediating intracellular redox-sensitive signal transduction. Here we show that hydrogen peroxide is also able to transmit pro-inflammatory signals from one cell to the other and that this action can be inhibited by extracellularly added catalase. If these data can be further substantiated, hydrogen peroxide might become as important as nitric oxide as a small molecule intercellular (first) messenger

Are ‘healthy cohorts’ real-world relevant? Comparing the National Child Development Study (NCDS) with the ONS Longitudinal Study (LS)

Comparisons between cohort studies and nationally representative ‘real-world’ samples are limited. The NCDS (1958 British birth cohort) follows those born in Britain in a single week in March 1958 (n=18,558); and the ONS Longitudinal Study (LS) contains linked census data and life events for a 1% sample of the population of England and Wales (> 1 million records; allowing for sub-samples by age, ethnicity, or other socio-demographic factors). Common country-and age-matched socio-demographic variables were extracted from the closest corresponding time-points, NCDS 55-year survey in 2013 (n=8107) and LS respondents aged 55 in 2011 (n=7052). Longitudinal associations between socio-demographic exposures (from the NCDS 46-survey in 2004 and LS respondents aged 45 in 2001) and long-term limiting illness (from NCDS 2013 and LS respondents 2011, aged 55) were assessed using logistic regression. The NCDS 55-year sample had similar characteristics to LS respondents aged 55 for sex and marital status, but the NCDS sample had lower levels of long-term limiting illness (19.7% vs 22.8%), non-white ethnicity (2.1% vs 11.7%) and living in South England (46.9% vs 50.1%), and higher levels of full-time employment (61.2% vs 55.2%), working in professional/higher managerial occupations (35.7% vs 29.2%), and living with a spouse (69.1% vs 64.9%), all p0.09) suggesting these NCDS findings are largely generalisable to the population of England and Wales