Fragments are frequently evaluated in terms of the number of
non-hydrogen atoms, and the lightest element commonly found in drugs is carbon.
In a sense, then, a methyl group is the smallest possible fragment. Indeed,
molecular modelers often use methyl groups as probes to sample a protein
surface, and medicinal chemists fantasize about the “magic methyl” that will
give a huge pop in potency. But how much affinity can a methyl group really
give you? William Jorgensen and colleagues at Yale attempt to answer this question in a recent issue of J. Med.
Chem.
The team analyzed every single paper published in J. Med. Chem. and Bioorg. Med. Chem. Lett. between 2006 and 2011 (ah, the joys of
being a grad. student!) This produced a data set of 2145 examples in which
researchers had replaced a hydrogen atom with a methyl group and reported
dissociation or inhibition constants for both ligands; more than 100 different
proteins were represented. Jorgensen and colleagues then plotted the change in
free energy (∆∆G) for the hydrogen to
methyl replacement.
The result was a roughly Gaussian distribution with a median
of 0.0 kcal/mol. In other words, on average, adding a methyl neither improved
nor decreased affinity. However, with a standard deviation of 1.0 kcal/mol, it
was fairly common to get a 5-fold boost in affinity. But the frequency dropped
off quickly from there: a 10-fold improvement occurred about 8% of the time,
and the prized 100-fold boosts happened only 0.4% of the time – often enough to
gain a persistent foothold in the imagination, but certainly not something
you’d want to count on. To yield a 100-fold improvement, each methyl has a
group ligand efficiency of 2.7 kcal/mol/atom, which is more than the Kuntz limit!
But higher boosts are possible: in a handful of cases the
gain in potency was more than 180-fold, and much of the paper focuses on four
of these truly magic methyls. A combination of crystallography and high-level
molecular modeling revealed that ideal hydrophobic interactions were
responsible for some of the affinity, but in all cases the methyl group also
preorganized the conformation of the ligand to optimize interactions with the
protein. The authors conclude:
It appears that to
reach the 10-fold level, placement of a methyl group in a hydrophobic environment
may be adequate; however, to go beyond that, the methyl group also generally
needs to induce a propitious conformational change. This is typically achieved
by ortho methylation in biaryl
systems or by branching at an atom attached to a ring.
Interestingly, these conformational changes make the
molecules less flat – more support for including three-dimensional fragments in
your collection.
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5 comments:
Conformational effects like those described in the paper can be exploited in design (as opposed to rationalising after the event) if one recognises strain in the bound conformation. Similar reasoning can be applied to tautomeric and ionisation states of bound ligands (it all just energy). People following this post might want to have a look at our PTP1B article:
http://dx.doi.org/10.1016/j.bmcl.2005.03.068
in which we used methoxy to apply the conformational lock.
The comment about the joys of being a grad student prompts me to mention that Matched Molecular Pair Analysis can be used to find all the methyl/des-methyl pairs in a database (I'd guess that the data used bu the Yale group would have been in WOMBAT) and I'll direct you to a recent review by some of my AZ friends:
http://dx.doi.org/10.1021/jm200452d
You can find magic methyls using MMPA but you can also look for less obvious relationships between structures (e.g. what is the largest difference in solubility between pairs of 'reversed' amides?)
I would like to weigh in on the 2D vs. 3D debate. My feeling about 3D fragments is that you would rather NOT lock in the conformation, but consider that a feature of the 3D fragment: you can sample 3D space with it, but as pointed out in this paper (and by Dr. Pete), try to lock down conformation as a contributor to binding energy.
So, of course the other question I am curious about is NOT the "Magic Methyl", but the "Super-Atom". If you change a carbon for N or O, theoretically you can pick up a hydrogen bond and get 1.4kCal of energy, which is enough to 10x boost in binding...
Do these results argue for including more methyl-substituted fragments in the initial screen or for doing more SAR follow-up with such compounds?
I'd say it depends on the fragments - compounds which can sample conformational space are good but if they sample too much then the entropic contributions are going to be to much to see anything, so key methyls may give you a set of fragments which sample different sections of space.
I once had the chemists at Roche place a method between two meta groups to block them sampling the space between and got a 1.5 log increase in potency. I was able to deduce from various bits of data that the binding space was an "out-out" conformation.
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