6 research outputs found
Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses
The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks. © 2021 The Author
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
How to Catch the Ball: Fullerene Binding to the Corannulene Pincer
The corannulene pincer (also known in the literature as the buckycatcher) is a fascinating system that may encapsulate, among other molecules, the C60 and C70 fullerenes. These complexes are held together by strong π-stacking interactions. Although these are quantum mechanical effects, their description by quantum chemical methods has proved very hard. We used three semi-empirical methods, PM6-D3H4X, PM6-D3H+ and GFN2-xTB, to model the interactions. Binding to fullerenes was extended to all open conformations of the buckycatcher, and with the proper choice of solvation model and partition functions, we obtained Gibbs free energies of binding that deviated by 1.0–1.5 kcal/mol from the experimental data. Adding three-body dispersion to PM6-D3H+ led to even better agreement. These results agree better with the experimental data than calculations using higher-level methods at a significantly lower fraction of the computational cost. Furthermore, the formation of adducts with C60 was studied using dynamical simulations, which helped to build a more complete picture of the behavior of the corannulene pincer with fullerenes. We also investigated the use of exchange-binding models to recover more information on this system in solution. Though the final Gibbs free energies in solution were worsened, gas-phase enthalpies and entropies better mirrored the experimental data
Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities
The inhibition of p53-MDM2 interaction is a promising new
approach to non-genotoxic cancer treatment. A potential application for drugs
blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the
occurrence of wild type p53 (wt p53) in the majority of patients. Although there
are very promising preclinical results of several p53-MDM2 antagonists in early
development, none of the compounds have yet proven the utility as a next
generation anticancer agent. Herein we report the design, synthesis and
optimization of YH239-EE (ethyl ester of the free carboxylic acid compound
YH239), a potent p53-MDM2 antagoniz
ing and apoptosis-inducing agent
characterized by a number of leukemia cell lines as well as patient-derived AML
blast samples. The structural basis of the interaction between MDM2 (the p53
receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a
prodrug and is the most potent compound that induces apoptosis in AML cells and
patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further
investigation and progression of YH239-EE
Novel trypanocidal inhibitors that block glycosome biogenesis by targeting PEX3–PEX19 interaction
Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development