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

Copper(II) Complexes with Highly Water-Soluble l- and d‑Proline–Thiosemicarbazone Conjugates as Potential Inhibitors of Topoisomerase IIα

Two proline–thiosemicarbazone bioconjugates with excellent aqueous solubility, namely, 3-methyl-(<i>S</i>)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [l-Pro-FTSC or (<i>S</i>)-H₂L] and 3-methyl-(<i>R</i>)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [d-Pro-FTSC or (<i>R</i>)-H₂L], have been synthesized and characterized by elemental analysis, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, and electrospray ionization mass spectrometry. The complexation behavior of l-Pro-FTSC with copper­(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV–vis spectrophotometry, electron paramagnetic resonance, ¹H NMR spectroscopy, and spectrofluorimetry. By the reaction of copper­(II) acetate with (<i>S</i>)-H₂L and (<i>R</i>)-H₂L in water, the complexes [Cu­(<i>S</i>,<i>R</i>)-L] and [Cu­(<i>R</i>,<i>S</i>)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu­(<i>S</i>,<i>R</i>)-L] showed the formation of a square-pyramidal complex, with the bioconjugate acting as a pentadentate ligand. Both copper­(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited Topoisomerase IIα activity in a DNA plasmid relaxation assay