Eating A Whole Bunch of Random Compounds

Reader Andy Breuninger, from completely outside the biopharma business, sends along what I think is an interesting question, and one that bears on a number of issues: A question has been bugging me that I hope you might answer. My understanding is that a lot of your work comes down to taking a seed molecule and exploring a range of derived molecules using various metrics and tests to estimate how likely they are to be useful drugs. My question is this: if you took a normal seed molecule and a standard set of modifications, generated a set of derived molecules at random, and ate a reasonable dose of each, what would happen? Would 99% be horribly toxic? Would 99% have no effect? Would their effects be roughly the same or would one give you the hives, another nausea, and a third make your big toe hurt? His impression of drug discovery is pretty accurate. It very often is just that: taking one or more lead compounds and running variations on them, trying to optimize potency, specificity, blood levels/absorption/clearance, toxicology, and so on. So, what do most of these compounds do in vivo? My first thought is "Depends on where you start". There are several issues: (1) We tend to have a defined target in mind when we pick a lead compound, or (if it's a phenotypic assay that got us there), we have a defined activity that we've already seen. So things are biased right from the start; we're already looking at a higher chance of biological activity than you'd have by randomly p...
Source: In the Pipeline - Category: Chemists Tags: Drug Assays Source Type: blogs