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 picking something out of a catalog or drawing something on a board.
And the sort of target can make a big difference. There are an awful lot of kinase enzymes, for example, and compounds tend to cross-react with them, at least in the nearby families, unless you take a lot of care to keep that from happening. Compounds for the G-protein coupled biogenic amines receptors tend to do that, too. On the other hand, you have enzymes like the cytochromes and binding sites like the aryl hydrocarbon receptor – these things are evolved to recognize all sorts of structually disparate stuff. So against the right (or wrong!) sort of targets, you could expect to see a wide range of potential side activities, even before hitting the random ones.
(2) Some structural classes have a lot more biological activity than others. A lot of small-molecule drugs, for example, have some sort of basic amine in them. That’s an important recognition element for naturally occurring substances, and we’ve found similar patterns in our own compounds. So something without nitrogens at all, I’d say, has a lower chance of being active in a living organism. (Barry Sharpless seems to agree with this). That’s not to say that there aren’t plenty of CHO compounds that can do you harm, just that there are proportionally more CHON ones that can.
Past that rough distinction, there are pharmacophores that tend to hit a lot, sometimes to the point that they’re better avoided. Others are just the starting points for a lot of interesting and active compounds – piperazines and imidazoles are two cores that come to mind. I’d be willing to bet that a thousand random piperazines would hit more things than a thousand random morpholines (other things being roughly equal, like molecular weight and polarity), and either of them would hit a lot more than a thousand random cyclohexanes.
(3) Properties can make a big difference. The Lipinski Rule-of-Five criteria come in for a lot of bashing around here, but if I were forced to eat a thousand random compounds that fit those cutoffs, versus having the option to eat a thousand random ones that didn’t, I sure know which ones I’d dig my spoon into.
And finally, (4): the dose makes the poison. If you go up enough in dose, it’s safe to say that you’re going to see an in vivo response to almost anything, including plenty of stuff at the supermarket. Similarly, I could almost certainly eat a microgram of any compound we have in our company’s files with no ill effect, although I am not motivated to put that idea to the test. Same goes for the time that you’re exposed. A lot of compounds are tolerated for single-dose tox but fail at two weeks. Compounds that make it through two weeks don’t always make it to six months, and so on.
How closely you look makes the poison, too. We find that out all the time when we do animal studies – a compound that seems to cause no overt effects might be seen, on necropsy, to have affected some internal organs. And one that doesn’t seem to have any visible signs on the tissues can still show effects in a full histopathology workup. The same goes for blood work and other analyses; the more you look, the more you’ll see. If you get down to gene-chip analysis, looking at expression levels of thousands of proteins, then you’d find that most things at the supermarket would light up. Broccoli, horseradish, grapefruit, garlic and any number of other things would kick a full expression-profiling assay all over the place.
So, back to the question at hand. My thinking is that if you took a typical lead compound and dosed it at a reasonable level, along with a large set of analogs, then you’d probably find that if any of them had overt effects, they would probably have a similar profile (for good or bad) to whatever the most active compound was, just less of it. The others wouldn’t be as potent at the target, or wouldn’t reach the same blood levels. The chances of finding some noticeable but completely different activity would be lower, but very definitely non-zero, and would be wildly variable depending on the compound class. These effects might well cluster into the usual sorts of reactions that the body has to foreign substances – nausea, dizziness, headache, and the like. Overall, odds are that most of the compounds wouldn’t show much, not being potent enough at any given target, or getting high enough blood levels to show something, but that’s also highly variable. And if you looked closely enough, you’d probably find that that all did something, at some level.
Just in my own experience, I’ve seen one compound out of a series of dopamine receptor ligands suddenly turn up as a vasodilator, noticeable because of the “Rudolph the Red-Nosed Rodent” effect (red ears and tail, too). I’ve also seen compound series where they started crossing the blood-brain barrier more more effectively at some point, which led to a sharp demarcation in the tolerability studies. And I’ve seen many cases, when we’ve started looking at broader counterscreens, where the change of one particular functional group completely knocked a compound out of (or into) activity in some side assay. So you can never be sure. . .