ChEMBL

When a screen and follow-up have failed to deliver an attractive lead for a 'hard' target, talk amongst the team often turns to running a screen for an allosteric inhibitor; Allosteric regulators are therefore a seductive/tantalising approach to find leads against tough targets such as protein-protein interactions, highly polar binding sites, etc.

But, there's a few hard questions to answer, this is just a few.

• Just how do I run a screen for an allosteric inhibitor?
• What compounds do I select for allosteric sites?
• How likely am I to find an allosteric inhibitor? 
• What sorts of targets can be allosterically modulated?
• What are the 3-D properties of allosteric sites

I've read some of the literature behind the arguments for allosteric inhibitors, and I must say I'm not that convinced as to their general potential benefits at the moment - of course in some cases, they will be perfect, but are the advantages as general as people may think. But I've been wrong, so many times in my life by now, that it's always worth looking at the actual data. So, as part of the SMS-Drug project we're putting together (and here 'we' means Gerard) of an overview of allosteric binders within ChEMBL - hopefully leading to some annotation of the class of binding of compounds to their targets.

Here (below, click for larger), is an initial overview of the target classes from ChEMBL for which we find evidence of allosteric regulation - this is not the same as the a priori distribution of targets, and so it looks interesting.....