2 research outputs found
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
Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing
Two-cysteine
peroxiredoxins (Prx) have a three-step catalytic cycle
consisting of (1) reduction of peroxide and formation of sulfenic
acid on the enzyme, (2) condensation of the sulfenic acid with a thiol
to form disulfide, also known as resolution, and (3) reduction of
the disulfide by a reductant protein. By following changes in protein
fluorescence, we have studied the pH dependence of reaction 2 in human
peroxiredoxins 1, 2, and 5 and in <i>Salmonella typhimurium</i> AhpC and obtained rate constants for the reaction and p<i>K</i><sub>a</sub> values of the thiol and sulfenic acid involved for each
system. The observed reaction 2 rate constant spans 2 orders of magnitude,
but in all cases, reaction 2 appears to be slow compared to the same
reaction in small-molecule systems, making clear the rates are limited
by conformational features of the proteins. For each Prx, reaction
2 will become rate-limiting at some critical steady-state concentration
of H<sub>2</sub>O<sub>2</sub> producing the accumulation of Prx as
sulfenic acid. When this happens, an alternative and faster-resolving
Prx (or other peroxidase) may take over the antioxidant role. The
accumulation of sulfenic acid Prx at distinct concentrations of H<sub>2</sub>O<sub>2</sub> is embedded in the kinetic limitations of the
catalytic cycle and may constitute the basis of a H<sub>2</sub>O<sub>2</sub>-mediated redox signal transduction pathway requiring neither
inactivation nor posttranslational modification. The differences in
the rate constants of resolution among Prx coexisting in the same
compartment may partially explain their complementation in antioxidant
function and stepwise sensing of H<sub>2</sub>O<sub>2</sub> concentration