Submission Details

Design Rationale:

A library of 80k natural products from the ZINC database was docked against two SARS-CoV-2 Mpro structures. Due to the known flexibility of SARS-CoV(-2) Mpro,[1,2] two crystal structures were selected from the PDB to provide different overall active site geometries, 6Y2E and 6Y2G [3]. These and eleven more Mpro structures [4] from the PDB were overlaid so as to determine active site residues displaying the largest degree of disorder which were then used to define flexible side chains for inclusion in the docking calculations. Virtual docking was performed with Autodock Vina [5] using protein and MBC compound structures prepared using MGLtools [6], OpenBabel [7] and RDKit [8]. Docking was performed against both crystal structures with/without flexible active site side chains. The best compounds were selected based on overall docking scores and predicted bioavailability.[9] The structures in this submission are predicted to be absorbed in the GI tract and to cross the blood-brain barrier. In addition, all are listed as commercially available in the ZINC database. Note: Fragment x0072 is simply selected as a placeholder since all of these compounds are natural products and not designed based on the fragment library. 1. Lee, T., et al, J. Mol. Biol., 366, 916 (2007) 2. Wells, S. A., bioRxiv, (2020) DOI: 10.1101/2020.03.10.986190 3. Zhang, L., et al, Science, 368, 409 (2020) 4. 6LU7, 5R7Y, 5R7Z, 5R80, 5R81, 5R82, 5R83, 5R84, 6Y84, 6Y2E, 6Y2F, 6Y2G, 6M03 5. Trott, O. & Olson, A. J., J. Comput.Chem., 31, 455 (2010) 6. Morris, G. M., et al, J. Comput. Chem., 31, 2785 (2009) 7. O’Boyle, N. M., J. Cheminf., 3, 33 (2011) 8. RDKit: Open-source cheminformatics; http://www.rdkit.org 9. Daina, A. & Zoete, V., ChemMedChem, 11, 1117 (2016)

Inspired By:

AAR-POS-d2a4d1df-1