Innovation Pharmaceuticals Inc (IPIX)

[Hawrylukg1]

Results and Discussion

We docked a chemical library of 11,552 compounds (composed by FDA-approved, investigational and experimental drugs, cf. the Methods section for details) onto three different proteins of the SARS-CoV-2: the Mpro, the PLpro, and the S-protein. In all targets, molecules
were scored with the QM docking score (QMDS). 7 QM methods capture the underlying physics of the molecular system accounting for all energy contributions, including electronic polarization, covalent-bond formation, and charge transfer. 8 For each target, we then analyzed the 1% top-scoring molecule subset, selecting candidates in terms of their QMDS, the presence of key interactions with the receptor, and visual inspection.

For the Mpro, we used two experimental structures: Mpro bound to peptide N3 (PDB6LU7)18 and the unbound form of the protein (PDB 6YB7). The purpose of using two structures for docking is to account to some extent for protein flexibility by receptor ensemble docking. 19,20 After docking, scoring, and ranking the molecules of the chemical library on
each receptor, the hit-lists were merged and the best ranking pose for each molecule was kept (according to the merging-and-shrinking method21,22).

Self-docking of peptide N3 onto structure 6LU7 had a root-medium-square deviation (RMSD) of 1.7 Å (an excellent result for a peptide), while according to its QMDS, N3 was within the top 0.3% of the docked library; this is a simple but necessary validation of our approach. Following the criteria described above, we hereby describe a list of potential inhibitors: Ritonavir (DrugBank ID DB00503) (Figure 1), Indinavir (DB00224) and Lopinavir (DB01601), which are FDA-approved drugs which act as HIV protease inhibitors, and are used to treat HIV/AIDS; Brilacidin (ChEMBL ID CHEMBL2219413) (Figure 1) an investigational drug for the supportive care of mucositis, stomatitis, and head and neck neoplasms (interestingly, Brilacidin is being investigated for direct inhibition of SARS-CoV-2 (press release of April 6th, 2010 23); Samatasvir (CHEMBL3039519) an investigational drug that has been used in trials as a treatment for hepatitis C infection; CR665 (DB05155) an investigational drug for the development of highly selective peripheral ?-opioid receptor agonists.

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