In my previous post, I explained how we found the surrounding residues lining the catalytic site of the SARS-CoV-2 main protease (MPro) using the available crystal structure from the protein databank (PDB code: 7bqy). Following that step, we wanted to zoom in on a few MPro’s structures bound to inhibitors. We looked at MERS, SARS-CoV, and SARS-CoV-2. For all of these structural analyses, we looked at the 21 residues lining the catalytic site:Thr25, Leu27, His41, Cys44, Met49, Pro52, Tyr54, Phe140, Asn142, Ser144, Cys145, His163, His164, Met165, Glu166, Leu167, Pro168, His172, Asp187, Gln189, Gln192.
We created 2-dimensional (2D) ligand-protein interactions using the MPro’s crystal structures and their corresponding ligand (inhibitors) in Proteins.plus PoseView (https://proteins.plus/). In Figure 1 here (SARS-CoV-2 MPro PDB code 7bqy), and Figure 5 (SARS-CoV MPro PDB code 2gx4) and Figure 6 (MERS main protease PDB code 5wkj) of the Zenodo post method section, we show the catalytic site pockets and the positioning of ligands based on the available crystal structures. We highlighted the critical non-conserved residues in orange. Based on this analysis, medicinal chemists designing or optimizing compounds that bind at this site want to avoid interactions between broad-spectrum inhibitors and these mutation-prone positions.
Figure 1. (A) The catalytic site of SARS-CoV-2 MPro (PDB code 7bqy). (B) Non-conserved critical sidechains are highlighted in orange. Crystallized inhibitor: purple. (C) 2D interaction diagram of a SARS-CoV-2 MPro inhibitor (created using Proteins.plus PoseView, PDB code 7bqy). A non-conserved critical sidechain is highlighted in orange.
You can view the detailed method and ICM scripts in this Zenodo post here.
In my next post, I will explain how we looked at sequence diversity at the MPro catalytic site across SARS-CoV-2 samples and other coronaviruses.
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