https://orcid.org/0000-0002-3324-9000
Figures & data
Table 1. Information about the 10 compounds selected from the virtual screening of 408 935 lead-like molecules.
Figure 1. MACAW embeddings can help identify molecules able to bind to SARS-CoV-2 Mpro. (a) Precision-recall curve of a kNN hit classifier trained on MACAW embeddings applied to a test set of molecules. (b) A SVR regressor was also trained to predict pKi values for promising molecules. (c) We computationally screened a custom library of 408 935 lead-like molecules and prioritised 105 that both the classifier and the regressor considered promising (orange region). See Jupyter Notebook 1 for details.
Figure 2. Selected compounds inhibit the activity of SARS-CoV-2 Mpro. The hydrolytic activity of SARS-CoV-2 Mpro was measured in the presence of increasing concentrations of different test compounds. (a) Ebselen. (b) Compound 1. (c) Compound 2. (d) Compound 3. (e) Compound 4. (f) Compound 5. (g) Compound 6. (h) Compound 7. (i) Compound 8. (j) Compound 9. (k) Compound 10. (l) IC50 values for Ebselen, Compound 1, Compound 7, Compound 8, and Compound 9. The dose-response curves and IC50 values were determined by nonlinear regression. All data are shown as mean ± SEM, n = 3 biological replicates.
Figure 3. Spectra of compounds 2 and 7. UV-vis absorption spectra of compound 2 (a) and compound 7 (b). Fluorescence emission spectra of compound 2 (c) and compound 7 (d) at an excitation wavelength of 325 nm.
Figure 4. Addition of detergent does not affect the inhibition of SARS-CoV-2 Mpro by selected compounds. (a) The hydrolytic activity of SARS-CoV-2 Mpro was measured in the presence of increasing concentrations of ebselen. (b–e) IC50 values were determined in the presence and absence of 0.1% Triton X-100. (b) Compound 1. (c) Compound 7. (d) Compound 8. (e) Compound 9. (f) Autofluorescence of selected compounds at different concentrations. All data are shown as mean ± SEM, n = 3 biological replicates.
Figure 5. (a) Evaluation of cytotoxicity of compounds 1, 7, 8, and 9 on MRC-5 cells at 72 h post-treatment by MTT test, n = 3. (b) Effects of compounds 1 and 7 on the haemolysis of red blood cells compared to a positive control (T+, 10% Triton X-100) and a negative control (Untreated), n = 3.
Figure 6. Evaluation of antiviral activity of compounds 1 and 7. Effect of (a) compound 1 and (b) compound 7 on the cytopathogenic effect by coronavirus hCoV-229 at different viral loads, n = 3. (c) Tissue culture infectious dose (50%) (TCID50), defined as the dilution of the virus required to infect 50% of the cell culture, in the presence of different concentrations of compound 7, n = 3.
Figure 7. Docking results of N3, ebselen, and compound 7 against the catalytic site of Mpro. (a) Highest scoring pose (yellow) and the crystallographic N3 pose (green). (b) Highest scoring pose of ebselen. (c) Highest scoring pose of compound 7. (d–f) 2D interaction maps for the highest scoring poses of N3, ebselen and compound 7 with Mpro, respectively.
Figure 8. Docking results of ebselen and compound 7 in the region between domains II and III of Mpro. The best pose of ebselen (a) and compound 7 (d) in that site. 3D visualisation of the key residues involved in the interaction between Mpro and ebselen (b) or compound 7 (e). 2D interaction maps for the best poses of ebselen (c) and compound 7(f) on Mpro.
