Submission Details

Design Rationale:

The list of drugs designated as "approved" in the SUPERDRUG2 database (>3600) were subjected to screening by using molecular docking (AUTODOCK VINA and SMILES) for binding to the target: Mpro of SARS-CoV-2. The X-ray diffraction based structures of Mpro obtained from PDB were utilized as models for target structure. The the plasticity of the active site of the target Mpro was taken into account by use of multiple targets structures obtain from PDB: 6LU7, 5R82 and 6YB7. 5R82 was chosen for its high resolution and 6YB7 was chosen because it is the structure of the unbound form of this protease and 6LU7 was chosen because of the similarity of the bounding inhibitor N3 to potential therapeutic candidates under investigation. This hit was identified in the following report: Sekhar Talluri, “Molecular Docking and Virtual Screening based prediction of drugs for COVID-19”, Combinatorial Chemistry & High Throughput Screening (2020) 23: 1. https://doi.org/10.2174/1386207323666200814132149

Other Notes:

Saquinavir is an FDA approved anti-viral drug. Therefore, its pharmacokinetic and toxicity are well documented. Saquinavir was found to bind with high affinity to the different crystal structures of the target protease Mpro of SARS-CoV-2. Most of the other molecules that emerged in this screen had a much higher degree of structure dependent predicted variability. This indicates that Saquinavir has to potential to inhibit, after consideration of the plasticity of the binding site of Mpro and may also be effective against mutant forms of Mpro which may cause minor changes at the active site. Experimental data is pertaining to activity of saquinavir against SARS-CoV-2 has been reported, but these studies were carried out without use of ritonavir. In vivo testing of combination of saquinavir and ritonavir is recommended.

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