Some time ago I wrote about some atoms that I wish I could use. There are still other molecular fragments that Nature has neglected to provide, though, and I'm adding to the wish list:
First off, I'd like some groups that are plain linear spacers of different lengths. Ideally, we could stick these onto carbons and heteroatoms alike. As it stands, the only commonly available group that does this is an alkyne (a carbon-carbon triple bond), and those come with their own baggage. While there are drugs that have these groups in them, they're typically treated pretty roughly by the liver enzymes. A metabolically stable alkynish thing, of variable length, would be a wonderful thing. People have made various weirdo spacers out of small bicyclic systems, true, but the synthetic routes to them are beastly, with no improvement in sight. Until we can source these things by the kilo, drug companies aren't going to be interested.
Next, I'd like some six-membered heteroaromatic rings with something other than nitrogen in them. As it is, pyridines, pyrimidines, and pyrazines are given a real workout in drug discovery programs, and we'd love to have some more options. Unfortunately, the fabric of the universe hasn't accomodated us. If you put an oxygen in there instead, it has to take on a positive charge, and that gives you a highly reactive beast called a pyrylium. It's rare that you can get one of those into a bottle, and even if you did, sending one in for biological testing would be grounds for a referral to the HR department. I see that some zanies have tried, though.
Sulfur can do the same lively thing, although I've never actually seen any of those, and there's probably a good reason for that. Varioius sorts of aromatic rings with a phosphorus atom in them are known, but they're cranky and exotic, like a lot of phosphorus chemistry. Actually, a lot of phosphorus chemists are kind of that way, too, in my experience. Like a lot of phosphorus compounds, those aryls probably reek to the skies, too. As for phosphorus chemists reeking, I'd say my personal data set runs about fifty-fifty.
And finally, I'd also like some big, lumpy polar atoms. As it is, if you want to put a single lunker of an atom onto a molecule, you're looking at a bromine substitution. Iodine's possible and even larger, but those compounds are usually too unstable to sunlight to make good drugs, unless you're doing thyroid receptor ligands, where you might have to have them whether you feel like it or not. It's true that a trifluoromethyl group is kind of like a big halogen atom, too. But all these halogens make your molecule rather greasy, which is something we'd rather avoid. Something the size of a bromine that could hydrogen-bond and help its molecule go into aqueous solution would be a big hit. Quantum mechanics, being perverse, has not obliged.