Submission Details

Design Rationale:

The Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, has a collection of 350 natural products derived from marine sponges, plants and bacteria. Together with Dr Bruce Milne, University of Coimbra, Portugal (Bruce Milne bfmilne@gmail.com), we modelled this family of compounds into the two available SARS-CoV(-2) 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] and OpenBabel [7]. 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.[8] The top 20 compounds were selected based on their docking scores. The top 12 are predicted to be absorbed gastrointestinally and cross the blood-brain barrier and the next 8 are only predicted to be absorbed gastrointestinally. Given difficulties in obtaining solvents right now, we will weigh requisite amounts into glass vials and ship them to Anthony Aimon at Diamond. 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. Daina, A. & Zoete, V., ChemMedChem, 11, 1117 (2016)

Inspired By:

AAR-POS-d2a4d1df-1