Practical Cheminformatics

Like many other groups around the world, we've been doing some virtual screening on the SARS Cov-2 Main Protease (Mpro).  There are now a lot of crystal structures of Mpro available.  How do we decide which structures to use for docking?  We'd like to select a diverse set of protein conformations that will enable us to explore multiple binding site interactions.  In this post, I'll provide an overview of a Jupyter notebook that my colleague Nic Pabon put together to explore the Mpro crystal structures.  While this notebook is oriented toward Mpro, the techniques discussed here can be applied to any protein. In this notebook, Nic used the open-source, Prody toolkit to perform a number of analyses on the Mpro fragment structures recently released by the team at the Diamond Light Source .  The notebook begins with an overview of some of the basic capabilities available in Prody. Reading PDB files Properties (number of atoms, residues, chains) Per ato...

In a recent paper in the Journal of Medicinal Chemistry, Lewis Pennington, Ingo Muegge, and coworkers at Alkermes present an overview of Positional Analogue Scanning (PAS), a widely used technique in Medicinal Chemistry.  This is a simple, yet powerful, technique where one "walks" a particular substituent around the structure of a lead molecule and explores a variety of substitutions.   As an example, consider the case below from the paper where each aromatic "cH" is sequentially replaced with nitrogen. As Pennington and coworkers point out, these small changes can often have profound effects on the properties, metabolism, and biological activity of a molecule.  In addition to being able to generate ideas for new molecules, PAS  can be a powerful tool for computational chemists.  By generating a set of positional analogs, one can rapidly investigate how structural changes impact computed properties.  This information can be used to understand SAR ...

In a preprint posted on bioRxiv on April 5, 2020, Franck Touret and coworkers from Aix Marseille Université published the results from a SARS-CoV-2 cellular assay of 1520 compounds from the Prestwick Chemical Library, a collection of off-patent marketed drugs.  Unfortunately, the authors published the preprint without including the chemical structures of the compounds.   Fortunately, Brian Cole used a couple of databases to associate structures with this screening data and posted the revised data, as well as the scripts he used to do the annotation on GitHub .  This short post serves two purposes.  It highlights data that may be useful to those working on treatments for SARS-CoV-2.  It may be possible to associate this screening data with recently released biophysical data and obtain mechanistic insights.  The solution that Brian came up with is generally applicable,  and can be applied to the many cases where data is published without as...

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 hop...

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.  ...