So in my post the other day about halogen bonds, I mentioned my unease at sticking in things like bromine and iodine atoms, because of the molecular weight penalty involved. Now, it's only a penalty if you're thinking in terms of ligand efficiency - potency per size of the molecule. I think that it's a very useful concept - one that was unheard of when I started in the industry, but which has now made a wide impression. The idea is that you should try, as much as possible, to make every part of your molecule worth something. Don't hang a chain off unless you're getting binding energy for it, and don't hang a big group off unless you're getting enough binding energy to make it worthwhile.
But how does one measure "worthwhile", or measure ligand efficiency in general? There are several schools of thought. One uses potency divided by molecular weight - there are different ways to make this come out to some sort of standard number, but that's the key operation. Another way, though, is to use potency divided by number of heavy atoms. These two scales will give you answers that are quite close to each other if you're just working in the upper reaches of the periodic table - there's not much difference between carbon, nitrogen, and oxygen. Sulfur will start throwing things off, as will chlorine But where the scales really give totally different answers, at least in common med-chem practice, is with bromine and iodine atoms. A single bromine (edit: fixed from earlier "iodine") weighs as much as a benzene ring, so the molecular-weight-based calculation takes a torpedo, while the heavy atom count just registers one more of the things.
For that very reason, I've been in the molecular-weight camp. But TeddyZ of Practical Fragments showed up in the comments to the halogen bond post, recommending arguments for the other side. But now that I've checked those out, I'm afraid that I still don't find them very convincing.
That's because the post he's referring to makes the case against simple molecular weight cutoffs alone. I'm fine with that. There's no way that you can slice things up by a few mass units here and there in any meaningful way. But the issue here isn't just molecular weight, it's activity divided by weight, and in all the cases shown, the ligand efficiency for the targets of these compounds would have gone to pieces if the "smaller" analog were picked. From a ligand efficiency standpoint, these examples are straw men.
So I still worry about bromine and iodine. I think that they hurt a compound's properties, and that treating them as "one heavy atom", as if they were nitrogens, ignores that. Now, that halogen bond business can, in some cases, make up for that, but medicinal chemists should realize the tradeoffs they're making, in this case as in all the others. I wouldn't, for example, rule out an iodo compound as a drug candidate, just because it's an iodo compound. But that iodine had better be earning its keep (and probably would be doing so via a halogen bond). It has a lot to earn back, too, considering the possible effects on PK and compound stability. Those would be the first things I would check in detail if my iodo candidate led the list in the other factors, like potency and selectivity. Then I'd get it into tox as soon as possible - I have no feel whatsoever for how iodine-substituted compounds act in whole-animal tox studies, and I'd want to find out in short order. That, in fact, is my reaction to unusual structures of many kinds. Don't rule them out a priori; but get to the posteriori part, where you have data, as quickly as possible.
So, thoughts on heavy atoms? Are there other arguments to make in favor of ligand efficiency calculated that way, or do most people use molecule weight?