Building on the Fragments From the Diamond/XChem SARS-CoV-2 Main Protease (MPro) Fragment Screen (Part I)

Like many in the community, I've been spending time looking at the results of a fragment screen of the SARS-CoV-2 main protease (MPro) by the group at the Diamond Light Source.  I thought it might be useful to share some of the techniques and the code that I use when working with the results of fragment screens.  One of the first things I like to do is to virtually expand the fragment by adding a set of substituents and looking for ways that the fragment can be expanded to make new interactions and increase potency.

Once I've added the substituents, I'll generate 3D conformers for the resulting expanded fragments.  The conformers are constrained so that the coordinates of the fragment are fixed.  Since we've fixed the coordinates of the core fragment, we can trivially place these expanded fragments in the original binding site and evaluate their interactions.  This approach is similar to the one we described in a 2004 paper in J. Med. Chem. In this post, I'll desc…