AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not. New pharmaceuticals need to explore more complex chemical spaces, like artificial antibodies. So I think if there was anything simple that has this effect (the way, say, caffeine makes you wake up) we would know.
AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not.
I don’t know anything about pharma research or chemistry, but this smelled off. Asking a bunch of LLMs (o3, 2.5 Pro, 3.7 ET, Grok 3, r1), none of them agree (o3: “no—we are nowhere close… this confuses confuses a genuine slowdown in R&D productivity (Eroom’s law) with chemical or biological exhaustion”, 2.5 Pro: “largely inaccurate and overly pessimistic”, 3.7 ET: “deeply misleading. It fundamentally misunderstands both the state of pharmaceutical research and the nature of small molecule discovery”, etc).
I am no expert but this was pretty much what I heard over and over when working in contact with pharma people around e.g. cheminformatics ML workshops and such. I think it’s well possible that this was meant as shorthand for a more complex “of course there are still tons of molecules that however aren’t even worth the effort of trying to synthesise and test, but all the small (< 100 atoms) candidates that even make sense to try have been explored to death” statement. Like, obviously you can do a bunch of weird small metallorganics I guess but if your reasonable assumption is that all of them are simply going to wreck someone’s kidneys and/or liver that’s not worth pursuing.
Then of course there’s regulatory and research costs, and part of the problem can be simply a classic “Hubbert peak” situation where really it’s the diminishing returns on mining further the configuration space of those molecules that make it impractical.
Fair, though generally I conflated them because if your molecules aren’t small, due to sheer combinatorics the set of the possible candidates becomes exponentially massive. And then the question is “ok but where are we supposed to look, and by which criterion?”.
Thanks. One of the first places I’d look would be hormones, which IIUC don’t count as small molecules? Though maybe natural hormones have already been tried? But I’d wonder about more obscure or risky ones, e.g. ones normally only active in children.
Some would count as small (e.g. cortisol, testosterone). But there’s also protein hormones. Honestly dunno but I expect we’d understand the effects of those kinds of molecules fairly well, if only because almost for all of them there is a condition where you have too little or too much of it providing a natural experiment.
Hm. TBC, the broader category would be “molecule that would activate master regulation of one or more gene regulatory networks related to brain function”, e.g. a hormone but maybe also some other things.
AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not. New pharmaceuticals need to explore more complex chemical spaces, like artificial antibodies. So I think if there was anything simple that has this effect (the way, say, caffeine makes you wake up) we would know.
I don’t know anything about pharma research or chemistry, but this smelled off. Asking a bunch of LLMs (o3, 2.5 Pro, 3.7 ET, Grok 3, r1), none of them agree (o3: “no—we are nowhere close… this confuses confuses a genuine slowdown in R&D productivity (Eroom’s law) with chemical or biological exhaustion”, 2.5 Pro: “largely inaccurate and overly pessimistic”, 3.7 ET: “deeply misleading. It fundamentally misunderstands both the state of pharmaceutical research and the nature of small molecule discovery”, etc).
Maybe you meant something more nuanced?
I am no expert but this was pretty much what I heard over and over when working in contact with pharma people around e.g. cheminformatics ML workshops and such. I think it’s well possible that this was meant as shorthand for a more complex “of course there are still tons of molecules that however aren’t even worth the effort of trying to synthesise and test, but all the small (< 100 atoms) candidates that even make sense to try have been explored to death” statement. Like, obviously you can do a bunch of weird small metallorganics I guess but if your reasonable assumption is that all of them are simply going to wreck someone’s kidneys and/or liver that’s not worth pursuing.
Then of course there’s regulatory and research costs, and part of the problem can be simply a classic “Hubbert peak” situation where really it’s the diminishing returns on mining further the configuration space of those molecules that make it impractical.
That’s unexpected and interesting, thanks.
Perhaps you misread the OP as saying “small molecules” rather than “small set of molecules”.
Fair, though generally I conflated them because if your molecules aren’t small, due to sheer combinatorics the set of the possible candidates becomes exponentially massive. And then the question is “ok but where are we supposed to look, and by which criterion?”.
Thanks. One of the first places I’d look would be hormones, which IIUC don’t count as small molecules? Though maybe natural hormones have already been tried? But I’d wonder about more obscure or risky ones, e.g. ones normally only active in children.
Some would count as small (e.g. cortisol, testosterone). But there’s also protein hormones. Honestly dunno but I expect we’d understand the effects of those kinds of molecules fairly well, if only because almost for all of them there is a condition where you have too little or too much of it providing a natural experiment.
Hm. TBC, the broader category would be “molecule that would activate master regulation of one or more gene regulatory networks related to brain function”, e.g. a hormone but maybe also some other things.