The end of June brought me to
Brisbane for the fifth
FBDD-DU Conference, which was meeting for the first time
outside Melbourne. This was also my first FBDD-DU conference since
2019, and it
was nice to see a wide range of talks from around Australia and beyond. As
always, I won’t attempt to be comprehensive, so if you attended, please feel
free to add your observations.
Techniques
Experimental techniques received
considerable attention. Félix Torres (NexMR) described using an inexpensive
benchtop NMR that doesn’t require liquid helium. Fragments were screened using photochemically
induced dynamic nuclear hyperpolarization (
photo-CIDNP). The method is so rapid that it is limited more by sample handling than
data collection, and the Torres team is speeding things up using flow technology.
Right now photo-CIDNP is still very much DIY, but rumor has it that
Bruker may soon launch a photochemical module for their benchtop instrument.
We’ve
written about
high-throughput crystallographic screening at the Diamond Light Source, and
synchrotrons around the world are building similar platforms. Kate Smith
described integrated systems at the Swiss Light Source which automate
crystallization, fragment screening, data collection, and data processing. She
also described increasing automation of fragment screening using the
free-electron laser (FEL), which we wrote about
here. Current throughput is
around 40 compounds per day and requires large amounts of protein, but these
are still early days.
Australia is building their own high-throughput
crystallography platform, and various components were described by Roxanne
Smith (University of Melbourne), Gautham Balaji (Monash Univesrity), and Yogesh
Khandokar (ANSTO-Australian Synchrotron). Watch this space!
Speaking of Australia, Nyssa
Drinkwater described
Compounds Australia, a national repository of more than
2.5 million molecules, including several fragment collections. Members, who can
be from outside Australia, can store their own libraries within the facility to ease
collaborations with other groups, and they can also access public libraries of
compounds, including unusual Antipodean natural product extracts. I was
fortunate to be able to visit the facility at Griffith University and can
attest that it is easily the equal of those in large pharma.
Turning to mass spectrometry,
Sally-Ann Poulsen (Griffith University) described covalent library screening
against PRMT5, a target we’ve written about
here. Sally-Ann is also a pioneer
of (conventionally non-covalent)
native mass spectrometry, and she described
applying this methodology to screen small molecules against RNA.
But the star of the conference
was
SPR, appearing in multiple talks. Long-time readers may recall an instrument made by SensiQ, with its
gradient injection capability to accelerate data
collection. This is now marketed by Sartorius, and Lauren Hartley-Tassell
(Griffith University) described using it to screen a glycoprotein. The larger
plumbing in the instrument is less prone to clogging, and Lauren said it can
even accommodate screening of whole cells.
Anything to accelerate the (sometimes
painful) process of advancing fragments is always welcome. As Jason Pun (Monash
University) noted, eight of nine targets screened in Martin Scanlon’s group
started with fragments having affinities worse than 100 µM. Off-rate screening,
an SPR technique we wrote about
here, can rapidly identify more
potent molecules from crude reaction mixtures, but data processing can be
tedious. Jason described new software tools to automate this process, and
hopefully he will publish the methodology and code. (An aside: over coffee Yun
Shi of Griffith University noted that off-rate screening, or ORS, should really
be called off-rate constant screening, which would give the more amusing
acronym ORCS.)
Targets
Turning to targets, Ben Davis
(Vernalis) described a collaboration with Servier to advance oncology target
USP7
inhibitors from a literature fragment to a preclinical candidate. Crude
reaction mixture screening was used extensively, not just by SPR but even in
microsome stability studies. Unfortunately the project ended when on-target
toxicology effects emerged, which were perversely more severe in higher animal
species than they were in mice.
Yun Shi described finding tiny
heterocyclic fragments that react with the NAD
+ cofactor of
neurodegenerative target SARM1 in situ to generate a potent inhibitor, as we wrote about
here. Yun is using
19F NMR to follow the base-exchange
reaction to identify inhibitors to other glycohydrolases too.
Deaths due to
E. coli are –
somewhat surprisingly – more common than those caused by any other pathogen,
and Christina Spry described her work at the National Australian University to
discover inhibitors of the essential dephosphocoenzyme A kinase (GPCK) enzyme,
which catalyzes the final step in the synthesis of Coenzyme A (CoA). Fragment
screening by
DSF and NMR identified a weak (K
D=380 µM) binder, and
fragment growing has led to a low nanomolar inhibitor that is selective against
the human form of the enzyme.
Continuing the
E. coli
theme, several talks discussed efforts against the challenging bacterial
virulence target
DsbA, a twenty-year campaign in Martin Scanlon’s group at
Monash as noted by Yildiz Tasdan. The enzyme
has a shallow, hydrophobic active site, but the discovery of fragments binding
to a cryptic site and crude-reaction screening by ORS (ORCS?) and
affinity-selected mass spectrometry (ASMS) has finally led to molecules with
dissociation constants around 1 µM.
Finally, in his closing keynote
address Alvin Hung, who recently founded NeuroVanda, described a wide range of
fragment success stories, many of them covered on
Practical Fragments,
against targets including
pantothenate synthetase,
GSK3β,
PKC-ι, and
MNK1/2. Although structural enablement helped in
many cases, Alvin was not rigid about the need for atomic-level details: in
response to the question whether he would advance a fragment in the absence of
structure, he answered simply, “of course.” Perhaps it's time to redo my
poll on
this subject.
I’ll wrap up here, but if you
missed this or earlier events this year there are still a couple more
conferences in Boston, and 2025 is already starting to take
shape.
