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

Lipoprotein (a) in patients with aortic aneurysmal disease

Objective: Lipoprotein (a) is an independent risk factor for atherosclerosis. Atherosclerotic degeneration is usually found in abdominal aortic aneurysms (AAAs), whereas thoracic aortic aneurysms (TAAs) caused by aortic dissection are not suggested to be linked pathogenetically to atherosclerosis. Lipoprotein (a) was analyzed in patients with AAA and TAA and in healthy individuals in relation to the extent of atherosclerosis. Methods. Included in the case control study were patients with AAA (n = 75) and TAA with dissection (n = 39) and healthy control subjects (n = 43), for a total of 157 participants. Serum lipoprotein (a) was measured with nephelometry. Lipoprotein (a) levels were compared between age-matched and gender-matched paired samples of the three groups, and an association of lipoprotein (a), aortic aneurysm, and the extent of atherosclerosis was determined in multivariate analysis. Results. Median lipoprotein (a) levels of patients with AAA and TAA and of control subjects were 18.9 mg/dL (interquartile range [IQR

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

Background: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. Methods: In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32degreesC to 34degreesC, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. Results: Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups. Conclusions: In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality. Copyright (R) 2002 Massachusetts Medical Society