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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 22, 2013

The Theology of Ligand Efficiency

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Posted by Derek

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?

Comments (26) + TrackBacks (0) | Category: Drug Assays | Drug Development


1. SP on January 22, 2013 10:28 AM writes...

You can also do activity / surface area. Don't know if that helps bridge the divide, I haven't seen any data suggesting one way or the other.

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2. Matt D on January 22, 2013 10:33 AM writes...

The problem you describe is important if ligand efficiency is your only measure. But if that's true, you now have two problems.

In other words, the presence of bromine or iodine should raise a flag just as the presence of other problematic functional groups would. But I don't think that hazard should show up as a penalty in ligand efficiency. So I prefer number of heavy atoms in the denominator, rather than molecular weight.

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3. Mike W on January 22, 2013 10:36 AM writes...

Ultimately all these are proxies for size. Gravity is not a factor in chemistry or biology. Mass is generally a very good proxy.

The problem with bromine or iodine is that they are big AND don't offer much in the way of interactions. The polarizability per size of Cl is pretty reasonable - one can think of Cl as a very small aromatic ring - but Br and I are pretty crappy given how much space they take up. With comparable mass and size to that of an aromatic ring, which has far more interesting HOMO, LUMO, quadrupole moment, etc., they're just kind of a big nothing.

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4. Rhenium on January 22, 2013 10:42 AM writes...

I guess my follow up question is, why does thyroxine (the only iodide containing compound in the body I'm aware of) go to the trouble of having an iodide instead of simple chloride or bromide?
Surely if a fluoro group is good enough for a med chemist, it ought to be good enough for nature. ^_~

I'd google the answer myself, but I'm preparing for my lecture.

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5. Iridium on January 22, 2013 10:45 AM writes...

A few short comments:

- Potency is only one of the several parameters to optimize.

- LE is a guide that might help you to make molecules with a good set of properties but it is NOT a goal.
So discussing if we should consider molecular weight rather than N of heavy atoms for the calculation of the LE might be interesting but probably completely irrelevant in lead optimization.

- Heavy atoms impact also LogP, not only molecular weight.

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6. Bunsen Honeydew on January 22, 2013 11:11 AM writes...

I'm pretty sure you meant a single bromine weighs as much as a benzene ring, rather than iodine weighing the same.

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7. DCRogers on January 22, 2013 11:23 AM writes...

#4: I always assumed it was for steric bulk to force the two aromatic rings out-of-plane into an interesting and hard-to-obtain-otherwise configuration, but it was just my guess.

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8. Pete on January 22, 2013 12:23 PM writes...

You can think of molecular recognition in terms of molecules presenting their surfaces to each other and one can argue that scaling standard free energy of binding by molecular surface area (as suggested by SP #1) is the most fundamental. Generally I prefer to define efficiency metrics in terms of -log(potency or affinity) rather than free energy because (a) it forces a degree of honesty in reporting the nature of the assay result and (b) there are less units to get 'lost'.

I would challenge Mike W's (#3) comment "... aromatic ring which has far more interesting HOMO, LUMO, quadrupole moment". It is completely meaningless to talk about the components of molecules as having HOMO, LUMO or quadrupole moments.

If you think about affinity in terms of relationships between structures then you might compare the potency gains from adding the bromine with accompanying loss of (aqueous) solubility. From what I recall, matched molecular pair analysis shows that, on average, bromo-substitution is more of a solubility killer than chloro-substitution.

It might be worth asking ourselves to what extent does the value we place on ligand efficiency depend on the extent to which we believe that affinity is correlated with molecular size.

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9. Rutabaga on January 22, 2013 12:28 PM writes...

#4 Rhenium, interesting question. I bet it has something to do with the specialness of selenocysteine. Also, maybe the inability of T4 and T3 to cross a cell membrane or into the CNS in the absence of active transport is a feature rather than bug. It enables regulation of differential concentrations and T4 -> T3 conversion between different tissues and between neighboring cells.

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10. Curious Wavefunction on January 22, 2013 12:57 PM writes...

Does anyone know of a study analyzing what bromine does in protein-drug crystal structures? At least in some cases it might improve potency by displacing a water molecule.

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11. simpl on January 22, 2013 1:04 PM writes...

Thanks for the lucid explanation of ligand efficacy. I was wondering if iodine, forming weaker bonds, is also too easily metabolised to be a useful group. I only found iodo-nucleotides (and thyroxine, of course)in a quick search.

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12. LeeH on January 22, 2013 1:23 PM writes...

I'm not a big fan of ligand efficiency. I don't see the point of lumping two properties together (i.e. those that the chemist should be watching so that they don't stray into unfavorable territory) when they really should be watching many more (solubility, ADME, PK, etc...). If you're going to have a single number that describes the "desirability" of a compound it should include everything, otherwise leave them separate and get used to tracking multiple parameters.

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13. RM on January 22, 2013 1:59 PM writes...

I think the question is: what problem are you trying to get around by measuring ligand efficiency instead of just raw potency? Sure "make every part of your molecule worth something" seems good in abstract (certainly don't include things that are worthless), but if you add a morpholine to your compound and activity goes up 30%, is that bad if your compound is 250 g/mol but good if it's 350 g/mol? (Because that's what ligand efficiency would tell you about the situation)

What are you actually trying to get at with ligand efficiency vs. raw activity? Is it solubility? Is it cost of synthesis? Is it rates of metabolic degradation? Is it something else? (What's the drawback of big molecules that you're trying to avoid?)

Figure out what you're actually trying to measure with "ligand efficiency", and then figure out if a bromine acts more like an extra carbon atom or an extra phenyl group in that regard. Then you'll know if dividing by molecular weight or number of atoms is the appropriate thing to do.

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14. TX Raven on January 22, 2013 2:56 PM writes...

So, how does this crowd feel about normalizing in vitro potency by dividing by (say) plasma free fraction?

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15. Pete on January 22, 2013 3:13 PM writes...

I think that plasma protein binding needs to be seen in the broader context of distribution and I would not recommend using free fraction to normalise potency. This article may be of interest (NRDD 9, 929-939):

dx dot doi dot org slash 10.1038 slash nrd3287

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16. Carl Lumma on January 22, 2013 4:14 PM writes...

An interesting case study is Bromantane, a substituted amphetamine. The addition of bromine seems to make it stick around longer in certain synaptic situations, changing the duration and intensity of the drug's action compared to other amphetamines.

Prozac famously contains fluorine...

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17. R. Frechette on January 22, 2013 5:58 PM writes...

There are a variety of rules of thumb, guidelines, folklore, etc. regarding structural requirements/limitations that are useful generalities in drug discovery. However, it seems that getting too theological about such things can lead to missed opportunities. There are sufficient examples of marketed drugs that violate one or more 'important' rules while somehow still being reasonably safe and efficacious to support occasional adventures off the rules-bound path.

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18. Teddy Z on January 22, 2013 7:59 PM writes...

I don't sit here proposing that the molecular weight argument is actual to be taken seriously, but rather that arbitrary cutoffs are capricious and arbitrary (how's that for circularity?). Instead, I think the argument you make is correct, by and large, for C, N, O there is so little difference in MW. But what about S? Should it count twice (32 vs 16?). The purpose of LE with HAC is not to be a hard and fast rule, but instead make people understand that every heavy atom put on has a price. What you are essentially advocating is a free-market exercise to determine what that cost is. "How much are you willing to pay for this here atom right here?" Defaulting to heavy atom count is simplistic, but simplicity sometimes make more sense.

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19. Rock on January 22, 2013 10:44 PM writes...

I like to use LE early in a program, in the hit selection and hit-to-lead time frame. Since I avoid bromine and iodine, I also prefer to use HAC. I don't think a CF3 is as bad as the MW would suggest and it is a commonly used functional group. I use LLE in the mid-to-later stages of the program as you get closer to your target potency.

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20. Dan on January 23, 2013 12:27 AM writes...

The thing I like about ligand efficiency is, as Teddy says, its simplicity: just binding energy per non-hydrogen atom. Binding energy per unit of molecular weight seems more abstract. Hopefully you won’t find too many molecules with bromines or iodines, and you should probably put them in a separate list as you would with any other controversial moiety.

Another metric that seems useful is the lipophilicity-adjusted version of ligand efficiency, LLE(AT), which tries to strip out the binding energy of desolvation:

Note that, due to their higher ClogP values, bromine- or iodine-containing molecules will score worse.

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21. PyBOP on January 23, 2013 1:24 AM writes...

" 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."

Well, there is an approved drug containing two iodine atoms. And the list of side-effects certainly doesn't look too good...

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22. TX Raven on January 23, 2013 5:00 AM writes...


PyBOP... are you implying the side effects arise from the two iodine atoms in the molecule?

Are you willing to generalize from an N=1 to the whole chemical space?

"Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication."

Drug discovery is about trade offs....

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23. Lankers on January 23, 2013 7:42 AM writes...

Drugs that release iodine upon metabolism could cause thyroid dysfunction

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24. pharmacologyrules on January 23, 2013 8:23 AM writes...

ligan efficiency, rule of 5, free fractions, etc. etc. me thinks that too many people read about drug discovery and don't actually do it

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25. PyBOP on January 23, 2013 1:24 PM writes...


Sorry, I was in a bit of a hurry this morning, so my post had to be quite short.

You are certainly right that this a N=1 case and in arrhythmia you take what you can get (and hope for the best).

What I wanted to say is that

A: There might be some valuable information around, if Derek wants to look at PK/Tox-data

B: The effect of iodine-containing compounds on the thyroid has to be considered.
After all, the thyroid's main function is to attach and detach iodine atoms to/from aminoacids. So similar to metabolism in the liver (CYP-inhibition), metabolism in the thyroid could be problematic (as proven for amiodarone).

Besides this, some side-effects of amiodarone (skin coloration, corneal deposits, phototoxicity) are indeed commonly attributed to the iodine substituents.

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26. Sebastian on January 23, 2013 11:50 PM writes...

4-iodo-2,5-dimethoxyphenethylamine is an orrally active brainpenetrant psychedelic drug, that is safe judging by its popularity (for a long time now). Its corresponding amphetamine - DOI - is a more potent version used as PET- tracer and in behavioural pharmacology. N-benzylated 2C-I is becoming popular as a higly potent but not orally active psychedelic. One cannot just rule out iodo in CNS drugs IMO!

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