Yesterday’s mention of carbohydrates brings up another topic, one that was raised in the comments and in some email correspondence. Most drug companies with an internal screening collection are concerned, to some degree, about how greasy that collection has turned out to be. The concern comes from the general perception that the more hydrophobic a compound is, the harder it will be to progress to a drug. It would be safer to add a “past a certain limit” in that phrase somewhere, and it would also be safer to say that this rule is not as solid as some people believe it to be. At one point there was a lot of thought that polarity correlated pretty well with later PK and toxicity, but (as those links show) this is a more complicated story, although not everyone’s gotten that memo.
Rather than reopen that discussion, though, let’s come at the polar compound issue from another direction. In general, I think that the argument for having some more polar chemical matter is to be able to address a wider variety of binding sites. A look at (for example) antibiotics suggests that there are whole classes of useful drugs that are on the polar fringes of what medicinal chemists consider acceptable. We’re probably missing out by not having enough chemical matter in that region. (It’s worth remembering that even back in the early days of Lipinski’s “Rule of Five” that he explicitly noted that it did not seem to apply to antibiotics).
Naturally enough, one reason that there are so many comparatively hydrophobic species in the screening deck is that it’s been partially filled by all the med-chem optimization programs of years past, so you have a lot of later-stage analogs in there that may not be quite as “lead-like”. Another reason, which sounds like just an excuse but is pretty practical, when you get down to it, is that the more water-soluble compounds are harder to work with in the lab – harder to purify, harder to get concentrated down out of all that water, etc. So why not fix this by just buying a lot of more hydrophilic stuff? That’s not an unreasonable idea, on the face of it, but how well does it work?
Perhaps not as well as you’d want. I’m willing to bet that similar-sized collections of “rather polar” and “rather nonpolar” screening compounds will show quite different hit rates across most screens, with the advantage going to the greasier ones. Hydrophobicity is one of the most reliable ways to get potency, after all – if your compound wants to flee the solution state for the comfort of a binding site, that’s what potency is, and a lot of binding sites are friendlier than bulk solvent. That’s not always the best way to get said potency, since your compound may not be so particular about what ports it sail into, but it is straightforward.
And the hydrophilic compounds have some extra issues. If they’re happier out there in the aqueous solvent than usual, they have comparatively less reason to go anywhere else. To go somewhere else, they’re also going to have to shed some of those solvating water molecules, and that’s a complicated process. You have the enthalpy of favorable hydrogen bonds to give up, balanced by the possible entropic gains in letting those waters go (but that all depends on how ordered they are in the bulk solvent versus around your compound). On the receiving end, your polar compound is going to have to make some polar interactions with the binding site for the whole process to have any thermodynamic chance at all – the worst thing of all is to poke a hydrogen-bonding group into an unreceptive binding region. But those polar interactions are pickier than the hydrophobic ones. Hydrogen bonds in particular are quite directional, and one that just misses is probably going to be worse than one that never was there to form in the first place. It’s not that placement doesn’t matter with hydrophobic interactions, but on the whole, they do tend to be “blobbier” than the polar ones.
So while I think that adding a bunch of polar chemical matter to the screening deck is a good idea, it’s not going to be any kind of instant fix. Especially if you’re going to have to have (as I suspect) two, three, four times as many of those compounds as you do of the “regular” kind in order to have a real effect on your screening hits. That’s my hypothesis, anyway – I’m pretty sure that no one has managed to put so many of these into their collections yet, though. I note that the “dark chemical matter” paper, which talked about compounds that look fine but never seem to hit in assays, found that such compounds tended to be noticeably more polar and have fewer aromatic rings. This, I’d say, is not at all accidental. But as that paper noted, if you do get a hit from this part of the collection, it’s worth prioritizing, because chances are lower that it’s leading you on. And I’d say the same for any unusually polar compound (polyhydroxylic, etc.) So long as it’s not full of quinones or the short list of things that (most of us) would immediately run from, it’s worth prioritizing.
This kind of thinking has implications for the “unnatural natural product” field. Natural products themselves have had evolutionary optimization; that’s why they’re so special (for some definitions of “special”). But there have been moves to more randomly replicate those kinds of structures, with those kinds of properties, as a way of getting more diverse chemical matter. I’m sympathetic, but as mentioned, I think that if you’re going to put together a collection like this, you’d better be prepared to make it a lot larger than you’ve probably planned for.