As regular readers here know, we often discuss metrics because everyone uses them. Last year, agent provcateur Pete Kenny unleashed a broadside against those who defended metrics. This seems to be like the corpse flower that blooms once a year, stinks the place up, yet everyone runs to go see it. Well, recently Pete posted in the LI group: "Ligand efficiency validated fragment-based design?"and asked whether or not people agreed with the statement. This of course has inspired a wave of comments. I disagreed with the statement, but not for the "metrics suck" argument. I strongly urge people to go read the thread, unless of course you have something better to do.
To me, this is not about the validity of metrics. [Let me add here, that I prefer the "LEAN" metric (pIC50/HAC) because it can be done in your head on the fly.] I think people have a good understanding of what they do, their limitations, and their strengths. I disagreed with the statement because of the use of the word "validated". In the development world, we talk about our assays very specifically: they are qualified or validated. A validated assay is one that has been shown to be accurate, specific, reproducible, and rugged for the analyte in the concentration range to be measured. Put plainly, this means that if you expect to measure analyte X at 5 uM, you have to show that for all samples it will be measured in you can identify it, measure 5 uM accurately, and do it every time. That's a validated measurement. When you are qualifying an assay, the bar is much lower. An assay is considered qualified if it has been demonstrated to be "fit for purpose". Fit for purpose means that it will do the job, but you haven't beat the sugar out of it to make sure it is "valid". To me, ligand efficiency is fit for purpose of driving medchem decisions; it is qualified for that purpose, but not validated (N.B. I am not saying "not valid".)
Posts
