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Tonight seemed like a good time to start the series of posts on screening library design. For those of you who don’t know, I’m taking a year out to travel and am currently in Asuncion, Paraguay and it is currently raining heavily with excellent electrical activity. It’s not all holiday and I’ll be dropping in on friends in Brasil and Australia to see if I can make myself useful in their research groups. It’s also a good time to send best wishes to my friends who are currently attending the Gordon Research Conference on Computer Aided Drug Design.
The special issue of the Journal of Computer-Aided Molecular Design devoted to FBDD has just come out and this includes an article on screening library design that three of my friends and I put together. I’ll certainly be drawing on the article in the series of posts on screening library design but these should complement the article rather than reproduce it verbatim.
A good place to start is a graphic of the generalised work-flow for fragment based lead generation which illustrates the process from the perspective of the library designer. Both protein structures and known ligands can be used to select compounds for screening but selections can also be made generically. Note the colour-coding of the arrows which illustrate flows of compounds (red) and information (blue). You keep cycling around until you find something cool or your management runs out of patience.
The graphic represents a generalised work-flow and in some cases selections based on target and/or known ligands may not be made. There are a number of reasons why this may be the case. For example, there may not be any known potent ligands for the target. Also specialised screening technologies may require specialised library formatting which favours the use of generic screening libraries. Even with protein structures available, there is still a role for generic libraries because the current state of the art for fast prediction of binding affinity still falls short of what is required for selection of compounds for screening against an arbitrary target. That is not to say that docking, scoring and affinity prediction methods are completely useless but just that at this stage they represent a basket into which you would not want to put all your eggs. Deciding how many eggs to put in the ‘generic’ and ‘targeted’ baskets depends on how much you know (or think you know) about your target. My own view is that we’re still a long way off being able to usefully predict affinity and much of this is due to the difficulties in modelling the displacement of water molecules from contact with protein molecular surfaces. Time will tell and I’ll be delighted if somebody proves me wrong!
Blomberg et al, Design of compound libraries for fragment screening. JCAMD 2009, 23, 513-525 DOI