An old curse runs, "may you
live in interesting times." And 2020 has been interesting indeed. Amid all
the tumult, Practical Fragments will maintain its tradition of ending
the year with a post highlighting conferences and reviews.
Despite the travel restrictions
caused by COVID-19, some conferences did go ahead, adapted to online formats: I
highlighted CHI’s Fifteenth Annual Fragment-based Drug Discovery and their
Eighteenth Annual Discovery on Target. Although these were quite
successful, I think most of us are looking forward to returning to in-person
events sometime in the coming year.
Perhaps because so many people
were stuck working from home, the number of reviews of potential interest to fragment fans has soared to a record number of more than twenty. I’ve tried to group
these thematically.
General
If you’re looking for a concise
yet thorough review, Harren Jhoti and colleagues at Astex provide one in Biochem.
Soc. Trans. Harren is one of the pioneers of FBDD, and the review touches
on library design, detection of fragment binding, and fragment to lead
strategies. A review in Front. Mol. Biosci. by Qingxin Li (Guangzhou
Sugarcane Industry Research Institute) goes into more detail on fragment
screening, optimization, and biological targets.
For the past five years a few
fragment fanciers (myself included) have been writing annual reviews in J.
Med. Chem. covering fragment-to-lead success stories from the previous year,
each with a handy table showing fragment, lead, and key parameters. The 2018
edition, led by yours truly (Frontier Medicines), was published at the
beginning of the year, while the 2019 edition, led by Wolfgang Jahnke
(Novartis), just came out a few weeks ago. At the risk of self-promotion, both
are well worth perusing to see the growing diversity of targets and emerging
trends, such as covalent fragments.
Biophysics
Biophysical methods are by far
the most commonly used for finding fragments, and an excellent overview of
thermal shift, SPR, and NMR by Joe Coyle and Reto Walser (Astex) appears in SLAS
Discovery. The goal is “to help the anxious biophysicist withstand the
relentless unforeseen,” and the paper provides loads of practical advice. For
example, over more than 50 thermal shift screens, “we have never derived
anything useful from negative Tm shifts.” The researchers note that “SPR is
particularly user-friendly and particularly prone to artifact,
overinterpretation, and varying degrees of frustration.” As for validating
ligand-observed NMR hits crystallographically, rates range from 5% to 80%.
As we noted earlier this year,
crystallography is becoming increasingly dominant in fragment screening, and in
Molecules Laurent Maveyraud and Lionel Mourey (Université de Toulouse)
provide an overview of the process, covering theory, workflow, practical aspects,
pitfalls, examples, and other emerging methods. David Stuart and colleagues at
Diamond Light Source discuss structural efforts on SARS-CoV-2 proteins in an
open-access paper in Biochem. Biophys. Res. Commun. As of late October
this included more than 500 released structures of 16 different proteins. Efforts
against the main protease (which I reviewed in Nat. Commun.) have led to
molecules with mid-nanomolar activity, and the researchers rightly highlight
the worldwide collaboration that has led to such rapid progress.
NMR
NMR is of course a biophysical
technique, but there are so many papers this year that it makes sense to
group them into their own section. Ray Norton (Monash Institute of
Pharmaceutical Sciences) and Wolfgang Jahnke (Novartis) introduce a special
issue of J. Biomol. NMR focused on “NMR in pharmaceutical discovery and development”
by briefly summarizing the state of the art and introducing 13 articles, one of
which we covered previously and three of which are highlighted below.
“NMR in target driven drug discovery,
why not?” ask Gregg Siegal and collaborators at ZoBio and Gotham in an (open
access) J. Biomol. NMR review. In addition to characterizing small
molecules, proteins, and their interactions, the researchers present cases studies
in which NMR data has helped clarify a crystallographic protein-ligand structure,
or even suggested that the crystal structure represented at most a minor conformation
in solution.
In other words, NMR is “the swiss
army knife of drug discovery,” as Reto Horst and colleagues at Pfizer put it in
another J. Biomol. NMR review. The researchers describe successful NMR fragment
screens against difficult targets such as an ion channel and a large (145 kDa)
trimeric enzyme. They also make a good case for using NMR to determine the solution
conformations of small molecules early in a project, a strategy that has paid
off in more than 15 Pfizer projects over the past six years.
Benjamin Diethelm-Varela (University
of Maryland) focuses on using NMR for “fragment-based drug discovery of
small-molecule anti-cancer targeted therapies” in ChemMedChem. This is a
thorough yet accessible overview of FBDD, ligand- and protein-based NMR
methods, plus ten case studies. “A practical perspective on the roles of
solution NMR spectroscopy in drug discovery” is provided by Qinxin Li and CongBao
Kang (A*STAR) in Molecules. As the title suggests, this review is fairly
broad, and includes an interesting section on NMR screening in cells.
All these papers might have you
thinking that NMR is a “Gold Standard,” and that phrase does indeed appear in
the title of another Molecules review by Abdul-Hamid Emwas (King Abdullah
University of Science and Technology) and a multinational group of collaborators.
This is a large (66 page) monograph with 455 references and is particularly detailed
on various NMR techniques; if you want to see the pulse sequence of the HSQC experiment
or review the Einstein-Stokes equation this is the place to turn.
In addition to the six reviews on
NMR above, two specifically cover 19F NMR. The first, from the J.
Biomol. NMR special issue by Claudio Dalvit (Lavis) and colleagues, focuses
on fluorine NMR functional screening, or n-FABS. This paper provides an
excellent theoretical and practical overview of the technique, and includes a
handy table of 17 published case studies. And in Prog. Nuc. Mag. Res. Spect.
Peter Howe (Syngenta) reviews “recent developments in the use of fluorine NMR
in synthesis and characterization.” As the title suggests, much ground is
covered, from spectrometer technology to quantum chemistry calculations, and
there is a short section on fragment-based screening.
Computational
Turning to in silico techniques, Floriano
Paes Silva Jr. and collaborators at LaBECFar and several other (mostly)
Brazilian institutes provide an open-access overview in Front. Chem. After
summarizing FBDD they describe how computational techniques can help along the
way, from druggability prediction to docking, de novo design, and assessment of
ADMET properties and synthetic accessibility. The review ends with several case
studies.
In an open-access article in Drug
Disc. Today, Stefano Moro and colleagues at University of Padova focus on “the
rise of molecular simulations in fragment-based drug design.” This accessible
overview covers hotspot identification, hit identification and characterization,
and hit to lead optimization, and includes a nice section on free energy perturbation.
Other topics
Molecular properties are critical
for developing good drugs, and in J. Med. Chem. Christopher Tinworth (GlaxoSmithKline) and
Robert Young (Blue Burgundy) “appraise the rule of 5 with measured physicochemical data.” This
is packed full of good stuff including a supplementary table with calculated and
measured data for hundreds of compounds. The summary is that molecular weight
is much less important than (measured) lipophilicity and hydrogen bond donors. “Good
practice is all about compromise, aiming to maximize efficacy and efficiency
while navigating many potential pitfalls in molecular optimization.” People
sometimes obsess over rules vs guidelines, and the researchers close by stating
that “rules are for the obedience of fools and guidance of the wise.”
As a poll from several years ago
suggested, fragment linking tends to be less common than fragment growing, though
it can work spectacularly. In J. Med. Chem. Isabelle Krimm and colleagues
mostly at Université de Lyon review 45 successful fragment linking case studies
(though it would have been appropriate for them to acknowledge Practical
Fragments for the clearly borrowed table of clinical compounds). While by
no means exhaustive, this is a useful resource. Interestingly, only 20% of the
examples display superadditivity.
Target-guided synthesis (TGS) can
be thought of as a special case of fragment linking. In J. Med. Chem., Rebecca
Deprez-Poulain and colleagues at Université de Lille review kinetic TGS, in
which two components react irreversibly with one another in the context of a
protein to form a higher-affinity binder. Kinetic TGS may have some practical
advantages over reversible TGS (or dynamic combinatorial chemistry), but as the
researchers note most examples start with compounds larger than fragments, and
thus only 38% of examples lead to products with a molecular weight less than
500 Da. This could partly explain why only 6 of the 50 reported examples have
gone into animal studies.
Finally, György Keserű and
collaborators at the Hungarian Research Centre for Natural Sciences review
covalent fragment-based drug discovery in Drug Discovery Today (open
access). Library design and validation is well-covered, as are various methods
for screening covalent fragments, and there is a handy table of some four-dozen
published examples. Given the increasing popularity of covalent FBLD, this contribution
should be of wide interest.
When I wrote my concluding post
for 2019, COVID-19 was an obscure and nameless disease, and SARS-CoV-2 had not
even been identified. I ended with, "may 2020 bring wisdom, and
progress." We've gained both, though the cost has been incalculable. So
I'll just close this post by thanking you for reading and commenting.
1 comment:
Another great year of PF!
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