Large small molecule screens

Hello,

I was wondering if any of you have done large small molecule screens before. I run a Biacore 8K, and we have so far completed 2 large screens of over 2000 compounds, but there were some definite hiccups that were hard to overcome so I thought I'd see what strategies others have come up with. The biggest hurdle so far is what to do about "sticky" compounds, i.e. compounds that don't dissociate quickly enough and need to be regenerated. As we all know, finding proper regeneration conditions can be very individual and time consuming depending on the ligand-analyte binding pair. Of course, when setting up a large screen to run consecutively, all sensorgrams after a particularly "sticky" compound might be compromised.

Our current strategy is to run a "pseudo" dose response with 2 injections of the analyte at different concentrations and screen this way. Any thoughts or options we haven't thought of would be greatly appreciated.

Thanks!
Josh Knauer

Hi Josh,
I have no experience with compound screening but found this article.

1. Shepherd, C. A., Hopkins, A. L. and Navratilova, I.; Fragment screening by SPR and advanced application to GPCRs. Progress in Biophysics and Molecular Biology (116) 2–3: 113-123; 2014.

In addition look at

From other users I know that often compounds are dissolved in DMSO. As a 'regeneration' step you can inject a DMSO solution (10- 50%) to remove the compound from the sensor surface.

Kind regards
Arnoud