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Showing posts from August, 2018

Scaffold Hopping? It's Complicated

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As seems to be the case these days, this post was motivated by a comment I saw in the blogosphere.  In one of the myriad discussions on applications of AI in drug discovery, someone wrote: 
"I have yet to encounter a machine learning algorithm which predicts a true scaffold hop (say from Viagra to Cialis). From that standpoint, a tool like ROCS which looks at abstract but general features like shape and electrostatics is better than a lot of ML."
The comment got me thinking about something that has bugged me for a long time.   What exactly constitutes a scaffold hop?  Should we consider Viagra to Cialis a scaffold hop? (hint, I don't think so, stick with me and I’ll explain)  What is a scaffold hop? Let’s start by taking a step back and looking at some of the classic work of Hans-Joachim Böhm and Martin Stahl.  In their 2004 paper, Böehm and Stahl highlighted three different three-dimensional approaches to scaffold hopping.  


The scaffold replacement approach provided t…

Filtering Chemical Libraries

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This post was partially motivated by a recent post from Karl Leswing describing how to use the DeepChem package to do virtual screening on a large database.  As part of the tutorial, Karl used the HIV sample file that is part of the DeepChem distribution to build a model.  This model was then used to select compounds from the ZINC database.  The tutorial is nice and the methodology is explained in a manner that is easy to follow.  The problem is that the molecules selected by the model are not what I would consider "drug-like".





The molecules reported in Karl's post have aryl sulfonic acid groups.  In fact, molecule D has 2 sulfonic acids AND a thiol.  To someone who has spent a bit of time looking through HTS data, these molecules scream false positive.  If an enterprising young computational chemist were to take this set of hits to an experienced medicinal chemistry colleague, my guess is that he/she would simply shake his/her head and say something like "that'…