The winter solstice is behind us
in the Northern Hemisphere, which means 2022 is rapidly drawing to a close. As
we have
done for the past
decade,
Practical Fragments will spend this
last post of the year summarizing conferences and reviews.
The remarkable progress in
vaccines against SARS-CoV-2 allowed the full return of in-person conferences,
and it was nice to see folks at CHI’s
Discovery on Target in Boston and
Drug Discovery Chemistry in San Diego. Nearly twenty reviews of interest to this
readership were published, and these are covered thematically.
Targets
Several reviews cover the use of
FBLD to target antiviral and antibacterial targets. Sangeeta Tiwari and
colleagues at University of Texas El Paso cover both in an open access
Pharmaceuticals
review, focusing on tuberculosis and HIV, which often afflict the same
individuals, leading to worse outcomes. The paper includes several tables with
chemical structures, though the fragment origins of some molecules are not
apparent.
Tuberculosis is caused by
Mycobacterium
tuberculosis, but there are more than 170 known members of the
Mycobacteriaceae family. In an open access
Int J. Mol. Sci. paper, the
Tiwari group describes fragment-based approaches against these bugs. In
addition to multiple examples, the review provides summaries of fragment
finding methods and some of the challenges the field faces.
Another organism,
Pseudomonas
aeruginosa, infects the lungs of people with cystic fibrosis. In an
open access
Front. Mol. Biosci. paper, Tom Blundell and collaborators at
University of Cambridge summarize fragment-based campaigns against this
organism and its enzymes. The authors focus on structure-guided methods and note
that the work is “at an early stage” but encouraging.
Switching to mammalian targets, Katrin
Rittinger and colleagues at The Francis Crick Institute
review (open access)
applications of FBLD for targeting the ubiquitin system in
Front. Mol.
Biosci. The paper includes a nice table summarizing 15 examples that
includes target, enzyme class, fragment binding mode, detection methods, and
chemical structures of the fragment hit and optimized compound where
applicable. Many of these are covalent modifiers; more on that topic below.
Finally, Tarun Jha, Shovanlal
Gayen, and collaborators at Jadavpur University
discuss “recent trends in
fragment-based anticancer drug design strategies” in
Biochem. Pharm. In
addition to case studies (with chemical structures) of FBLD approaches against
18 oncology targets, the review covers fragment libraries, screening methods,
optimization, and challenges.
Methods
Many of the targets above are
challenging, and it’s always nice to be able to assess
how challenging a
project might be at the outset. In
Curr. Opin. Struct. Biol., Sandor
Vajda and collaborators at Boston University and Stony Brook University
discuss
(open access) “mapping the binding sites of challenging drug targets.” This is
a brief, readable account of computational methods to identify
hot spots,
including allosteric ones. The authors examine the various small-molecule
binding sites on
KRAS and conclude that, due to “limited druggability,” the
“other G12 oncogenic mutants will be very challenging.” Perhaps, but not
impossible, as researchers at Mirati demonstrated earlier this year with the
(open access)
publication of a low (or sub) nanomolar KRAS
G12D
inhibitor.
Among experimental methods used
in FBDD, NMR is a
mainstay, as
demonstrated by Luca Mureddu and Geerten Vuister
(University of Leicester) in
Front. Mol. Biosci. (open access). The
paper covers methods, successes, and challenges, focusing on three compounds
that reached the clinic: AZD3839,
venetoclax, and
S64315.
In contrast to NMR, dynamic
combinatorial chemistry (
DCC) and DNA-encoded libraries (
DEL) are used less frequently in FBLD. In
RSC Chem. Biol., Xiaoyu Li and
collaborators at University of Hong Kong and Jining Medical University
discuss
“recent advances in DNA-encoded dynamic libraries.” This concise paper covers
lots of ground and does not understate the challenges.
Libraries
“The importance of high-quality
molecule libraries” is emphasized by Justin Bower and colleagues at the Beatson
Institute in
Mol. Oncol. This highly readable and wide-ranging open access
review
covers all aspects of library design and use and includes comparisons of some
of the major commercial
vendors. An important point is that the “hit rate does
not define the success of a library as it is more important to identify
ligand-efficient and chemically tractable start points.”
Thus, even though shapely fragments
may have lower hit rates than more
planar aromatic fragments, they may still be
worth including – if you can make them. In
Drug Discov. Today (open
access), Peter O’Brien and collaborators at University of York and Vrije
Universiteit Amsterdam
review synthetic strategies behind 25 “3D” fragment
libraries. The tabular summary showing all the scaffolds emphasizes that most
of these libraries are modest in size, with the largest being 102 members.
Chemists will particularly enjoy the multiple synthetic schemes. The authors
note the importance of “
fragment sociability” to facilitate SAR and
elaboration.
Covalent fragments
Special libraries are required
for covalent fragment-based drug discovery, the most notable feature being the
“warhead” that reacts with the protein target. These are the focus of a
chapter
in
Adv. Chem. Prot. by Péter Ábrányi-Balogh and György Keserű of the
Hungarian Research Centre for Natural Sciences. The review includes a table
containing more than 100 warheads with associated mechanisms and amino acid selectivity.
The “reactivity of covalent
fragments and their role in fragment-based drug design” is the focus in an
(open access)
Pharmaceuticals review by Kirsten McAulay and colleagues
at the Beatson Institute. This is a nice overview of the field and contains
several case studies. The authors conclude that “striking a balance between
reactivity, potency and selectivity is key to identifying potential
candidates.”
“Advances in covalent drug
discovery” are
reviewed (open access) by Dan Nomura and colleagues at University
of California Berkeley in
Nat. Rev. Drug Disc. This is a highly readable
and comprehensive overview of the field. The authors differentiate between
“ligand-first” approaches, in which a covalent warhead is appended to a known
binder (such as
here) and “electrophile-first,” in which “the initial discovery
process is rooted in finding a covalent ligand from the outset,” such as for
KRASG12C inhibitors.
Another broad
overview of
covalent inhibitors is provided by Juswinder Singh (Ankaa Therapeutics) in
J.
Med. Chem. Jus is a
pioneer in the field, having
published the first
targeted covalent inhibitor in 1997. Of 1673 small molecules approved as drugs
by the US FDA, only about 7% are covalent, and it wasn’t until recently that
these have been intensively pursued. Part of the reluctance has been concerns
over toxicity, but the paper suggests that – at least among kinase inhibitors –
covalent drugs may actually be safer, perhaps due to conjugation of glutathione
to the warhead and rapid clearance rather than formation of reactive
metabolites.
Other
Whether covalent or not, thermodynamics
plays a fundamental role in protein-ligand interactions, and this is the topic
of an (open access)
review in
Life by Conceição Minetti and David Remeta
of the State University of New Jersey. The paper covers a lot of ground,
including drug discovery approaches,
metrics (such as
LE,
LLE, etc.),
isothermal titration calorimetry, case studies, and more. Importantly, the authors
acknowledge the many challenges of applying thermodynamics to drug discovery,
some of which we highlighted
here.
Thermodynamics explains the
potency increases
longed for when doing fragment-linking, the subject of two
reviews. In
Chem. Biol. Drug Des. Anthony Coyne and colleagues at
University of Cambridge provide a broad
overview, starting with the historical
theoretical background and newer
developments. The bulk of the paper surveys
published examples of fragment linking, with structure-based methods (whether
X-ray, NMR, or computational) separated from target-guided methods such as DCC.
The second
review, published in
Bioorg.
Chem. by Junmei Peng and colleagues at University of South China, is
broader in scope, encompassing not just FBLD but also linkers used in PROTACs
and even antibody-drug conjugates. The paper is organized by chemical structure
of the linker.
Finally, in
J. Med. Chem., Peter Dragovich,
Wolfgang Happ, and colleagues at Genentech and Roche
examine “small-molecule
lead-finding trends” at their organizations between 2009 and 2020. (Although
Genentech is fully owned by Roche, its research organization operates
independently.) Fragment-based approaches led to only a small fraction of
chemical series at Genentech and none at Roche. The authors note that leads
derived from public sources such as patent applications were often found and
pursued earlier, and that “purposeful dedication” of resources to fragment
approaches may be necessary. Another major source of leads at Genentech is in-licensing, and
some of these are fragment-derived.
And that’s it for 2022, year
three of COVID-19. Thanks for reading and special thanks for commenting. May
the coming year bring health, peace, and significant scientific progress.
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