Practical Cheminformatics

Introduction In my previous post , I showed how we could generate a bunch of ideas for expanding on one of the fragment hits from the screen of the SARS-CoV-2 Main Protease (MPro) conducted at the Diamond Light Source . In this post, we'll go through one method of rapidly evaluating these ideas.  In my previous posts, I've tried to use Open Source software wherever possible.  Here I'm going to make an exception and write all of the code using toolkits from OpenEye Scientific Software .  I'm doing this for a couple of reasons. I've been using some of these toolkits for 20 years.  I know them well, and it makes it easy for me to write and test the methodology.  I don't think that some of what I'm doing is possible, or at least easy to do, with Open Source software.  If someone has a similar Open Source workflow, please let me know.  I'd love to see it and try it.  A lot of people in the community are using the OpenEye toolkits and can hopefully use,

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