Hydrogen bond donors (HBDs) in
ligands are troublemakers. Having more than a couple tends to decrease permeability,
bioavailability, and even solubility. HBDs can also lead to efflux, which is
particularly problematic for drugs that must cross the blood-brain barrier. While
this is true in general, the problems become even more acute for heterobifunctional
drugs such as PROTACs, which contain two moieties that each recognize a separate
protein. To minimize the number of HBDs at the outset of a project, Benjamin
Whitehurst and colleagues at AstraZeneca have built a “Low HBD” fragment set,
which has just been described in J. Med. Chem. Soc.
The researchers started by
examining roughly 205,000 compounds in their collection having between 11 and
19 non-hydrogen atoms and no more than one HBD, defined as “a proton bonded to
an oxygen or nitrogen atom in its neutral form.” An extensive series of filters
was used to winnow the molecules based on physicochemical properties,
diversity, and absence of reactive groups. Consistent with our recent poll,
synthetic tractability was considered explicitly. The researchers also made use
of a multiparameter optimization score (see here). After quality control, which
included solubility and compatibility with SPR, they ended up with a set of 551
fragments.
AstraZeneca has recently revamped
their general purpose “Biophysics” fragment library, which consists of 2741
compounds. They also have a set of 402 “Kinase Hinge” fragments, which contain
hydrogen bond donors near hydrogen bond acceptors. Comparing the Low HBD set with the other two
revealed that it was as diverse as the Biophysics set and more diverse than the
Kinase Hinge set. Other parameters such as the number of hydrogen bond acceptors
(HBAs), polar surface area, and molecular weight were similar between the Low
HBD and Biophysics libraries. Happily, and perhaps defying expectations,
lipophilicity was not higher in the Low HBD set.
So how does the library perform?
The researchers describe five screens against an E3 ligase, a protein-protein
interaction, a kinase, a histone methyltransferase, and a transcription factor.
Confirmed hits (defined as having Kd < 1 mM by SPR) were obtained
for all targets. Hit rates for two targets were comparable to hit rates for the
Biophysics set, as were the dissociation constants and ligand efficiencies. Not
surprisingly the Kinase Hinge set produced a higher hit rate for the kinase. (Two
targets were only screened with the Low HBD set.)
The percentage of hits from the
other fragment libraries having 0 or 1 HBD was 44%, 46%, and 80%, so the Low
HBD set does seem to be fulfilling its role of enriching these types of
compounds. Interestingly, when the researchers analyzed successful fragment-to-lead studies published between 2015 and 2021, they found that 53% of them had just 0
or 1 HBD.
All these results suggest that
sharply curtailing the number of hydrogen bond donors in a fragment library
doesn’t have negative consequences. Perhaps this isn’t surprising: an analysis
we highlighted in 2021 based on 131 fragment-to-lead success stories noted that
most of them only retained one or two polar interactions from the initial hit. That
paper also noted that while 35% of the polar interactions were from N-H hydrogen
bond donors on the ligands, an even higher percentage came from hydrogen bond
acceptors. That paper and the AstraZeneca researchers also note the potential
of other types of interactions, such as polarized C-H hydrogen bond donors and halogen bonds. It will be fun to watch hits from this library progress.
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