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

The Misfolding Pathway of SOD1: Implications for Drug Design in ALS

With the development of modern medicine, many diseases and maladies have been eradicated or rendered non-fatal. This has allowed human beings to live longer and more comfortably. As the average lifespan has increased, however, diseases that tend to occur late in life have become more prominent. Neurodegenerative diseases, such as Alzheimerâ s disease and amyotrophic lateral sclerosis (ALS), affect the brain and nervous system, killing neuronal cells necessary for proper bodily function. In almost all cases, protein misfolding and the accumulation of aggregated material are involved in these toxic effects. In the case of ALS, protein misfolding and aggregation occur in motor neurons, causing them to die which leads to a progressive full-body paralysis and death by respiratory failure. In ~20% of ALS cases showing familial inheritance, over 180 mutations in the Cu, Zn superoxide dismutase protein (SOD1) have been recognized as causing the disease. These mutations do not have the common property of compromising the superoxide scavenging activity of this protein. Rather, mutations increase its propensity to adopt non-native conformations that acquire some toxic properties. The structures of the pathological misfolded protein are not known, but identifying them and the misfolding pathways that produce them are crucial for developing treatments that target the toxic conformations themselves or prevent SOD1 from misfolding and reaching those states. In this thesis, a battery of techniques was developed and applied to kinetically track multiple processes during SOD1 unfolding which has produced the most detailed mapping of the SOD1 misfolding pathway. Using this information, a computational screen was used to find molecules that might bind to and stabilize the dimer interface to prevent an early event in the pathway, dimer dissociation. Two molecules were found that inhibited misfolding and aggregation in vitro which may be the beginnings of a treatment for this currently incurable disease.Ph.D