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Fragment-based Drug
Discovery Literature to September
2007 © IOTA
Pharmaceuticals Ltd |
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Authors |
Journal |
Title |
Abstract |
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Abad-Zapatero C, Metz JT. |
Drug Discov Today. 2005 Apr
1;10(7):464-9. No abstract available. |
Successful drug discovery
involves the optimization of many variables, such as compound potency,
selectivity and solubility. Drug development is an arduous process, beginning
with lead selection and continuing through to preclinical testing in animal
models. Efficient navigation through these steps should be facilitated by
reducing the number of variables. |
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|
Adrian FJ, Ding Q, Sim T,
Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, Mestan J,
Fabbro D, Gray NS. |
Nat Chem Biol. 2006
Feb;2(2):95-102. Epub 2006 Jan 15. |
Allosteric
inhibitors of Bcr-abl-dependent cell proliferation. |
Chronic myelogenous leukemia
(CML) is a myeloproliferative disorder characterized at the molecular level
by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated
tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as
the target for the treatment of CML by imatinib, we sought to identify
pharmacological agents that could target this kinase by a distinct mechanism.
We report the discovery of a new class of Bcr-abl inhibitors using an
unbiased differential cytotoxicity screen of a combinatorial kinase-directed
heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive
antiproliferative activity toward Bcr-abl-transformed cells, with potencies
similar to imatinib, while showing no inhibition of the kinase activity of
full-length or catalytic domain of c-abl. We propose that this new class of
compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP
competitive mechanism. |
|
Andrews MJ, Kontopidis G,
McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM. |
Chembiochem. 2006
Dec;7(12):1909-15. |
REPLACE:
a strategy for iterative design of cyclin-binding groove inhibitors. |
We describe a drug-design
strategy termed REPLACE (REplacement with Partial Ligand Alternatives through
Computational Enrichment) in which nonpeptidic surrogates for specific
determinants of known peptide ligands are identified in silico by using a
core peptide-bound protein structure as a design anchor. In the REPLACE
application example, we present the effective replacement of two critical
binding motifs in a lead protein-protein interaction inhibitor pentapeptide
with more druglike phenyltriazole and diphenyl ether groups. These were
identified through docking of fragment libraries into the volume of the
cyclin-binding groove of CDK2/cyclin A vacated through truncation of the
inhibitor peptide-binding determinants. Proof of concept for this strategy
was obtained through the generation of potent peptide-small-molecule hybrids
and by the confirmation of inhibitor-binding modes in X-ray crystal
structures. This method therefore allows nonpeptide fragments to be
identified without the requirement for a high-sensitivity binding assay and
should be generally applicable in replacing amino acids as individual
residues or groups in peptide inhibitors to generate pharmaceutically
acceptable lead molecules. |
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Aronov AM, Bemis GW. |
Proteins. 2004 Oct
1;57(1):36-50. |
We present a novel method
for stepwise scaffold assembly that integrates fragment-by-fragment ligand
design approaches with high-throughput virtual library screening (COREGEN).
As an extension of our earlier studies of common features present in drug
molecules, we investigate the hypothesis that most pharmaceutically
interesting ligands can be expressed in terms of the ring-linker frameworks
that comprise them. Analysis of 119 published kinase inhibitors from at least
18 different targets illustrates that a basis set of 4 rings and 8 linkers is
sufficient to describe approximately 90% of ring and linker occurrences,
respectively. A similar result was derived from a larger set of approximately
40,000 kinase inhibitors from curated patents. A method for ring-linker-based
assembly of scaffold libraries that uses experimental information to guide the
placement of anchor fragments is validated using a set of reported kinase
inhibitors of Bcr-Abl, Cdk2, and Src. In every case, the predominant
structural motif of reported ligand cores is reproduced and variations are
suggested. To underscore generality of this approach, a novel scaffold for a
cyclooxygenase-2 (COX-2) selective ligand is proposed. |
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Babaoglu K, Shoichet BK. |
Nat Chem Biol. 2006
Dec;2(12):720-3. Epub 2006 Oct 29. |
Fragment-based screens test
multiple low-molecular weight molecules for binding to a target. Fragments
often bind with low affinities but typically have better ligand efficiencies
(DeltaG(bind)/heavy atom count) than traditional screening hits. This
efficiency, combined with accompanying atomic-resolution structures, has made
fragments popular starting points for drug discovery programs. Fragment-based
design adopts a constructive strategy: affinity is enhanced either by cycles
of functional-group addition or by joining two independent fragments
together. The final inhibitor is expected to adopt the same geometry as the
original fragment hit. Here we consider whether the inverse, deconstructive
logic also applies--can one always parse a higher-affinity inhibitor into
fragments that recapitulate the binding geometry of the larger molecule?
Cocrystal structures of fragments deconstructed from a known beta-lactamase
inhibitor suggest that this is not always the case. |
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Bailey D, Zanders E, Dean P. |
Pharmacogenomics J.
2001;1(1):38-47. |
Site-specific
molecular design and its relevance to pharmacogenomics and chemical biology. |
The emergence of the new
discipline of pharmacogenomics reflects the growing convergence of chemical
and genomic space. The massive information-driven growth in both
computational chemistry and structural biology is leading to unprecedented
opportunities in both chemical and biological design. In this paper we relate
current opinion in structural biology to recent developments in computational
drug design. Sequence information now permits protein structure prediction
and, together with experimental protein structure determination, a complete
database of ligand-binding sites and protein-protein interactions can be
assembled. When aligned with site exploration and virtual screening, this
information provides a foundation for structure-based pharmacogenomics. In
association with chemical genomics, structure-based design will allow major
new insights into a compound's biological and pharmaceutical properties. |
|
Bailey D, Zanders E, Dean P. |
Nat Biotechnol. 2001
Mar;19(3):207-9. No abstract available. |
[No abstract] |
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Barakat MT, Dean PM. |
J Comput Aided Mol Des. 1995
Oct;9(5):457-62. |
The fragment placement
method has been successfully extended to the problem of envelope-directed
design. The atom assignment paradigm was based on molecular similarity
between two molecular structures. A composite supersurface is defined to form
the surface onto which the molecular fields are projected. The assignment
process is then determined by using molecular similarity in the objective
function to be optimized. In principle, this procedure is closely similar to
that outlined in the previous paper for site-directed design. The rationale
has been extensively tested on two benzodiazepine antagonists believed to bind
to the same site. |
|
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Barakat MT, Dean PM. |
J Comput Aided Mol Des. 1995
Oct;9(5):448-56. |
Three previous papers in
this series have outlined an optimization method for atom assignment in drug
design using fragment placement. In this paper the procedure is rigorously
tested on a selection of five ligand-protein co-crystals. The algorithm is
presented with the molecular graph of the ligand, and the
electrostatic/hydrophobic potential of the site, with the aim of creating a
placement on the molecular graph which is as electrostatically complementary
or hydrophobically similar to the site as possible. Various designer options
were tested, including, where appropriate, hydrogen bonding and a restricted
number of halogens. In most cases, the placement obtained was at least as
good as the native ligand, if not significantly better. |
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Barakat MT, Dean PM. |
J Comput Aided Mol Des. 1995
Aug;9(4):359-72. |
Atom assignment onto 3D
molecular graphs is a combinatoric problem in discrete space. If atoms are to
be placed efficiently on molecular graphs produced in drug binding sites, the
assignment must be optimized. An algorithm, based on simulated annealing, is
presented for efficient optimization of fragment placement. Extensive tests
of the method have been performed on five ligands taken from the Protein Data
Bank. The algorithm is presented with the ligand graph and the electrostatic
potential as input. Self placement of molecular fragments was monitored as an
objective test. A hydrogen-bond option was also included, to enable the user
to highlight specific needs. The algorithm performed well in the
optimization, with successful replications. In some cases, a modification was
necessary to reduce the tendency to give multiple halogenated structures.
This optimization procedure should prove useful for automated de novo drug
design. |
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Barakat MT, Dean PM. |
J Comput Aided Mol Des. 1995
Aug;9(4):351-8. |
If atom assignment onto 3D
molecular graphs is to be optimized, an efficient scheme for placement must
be developed. The strategy adopted in this paper is to analyze the molecular
graphs in terms of cyclical and non-cyclical nodes; the latter are further
divided into terminal and non-terminal nodes. Molecular fragments, from a fragments
database, are described in a similar way. A canonical numbering scheme for
the fragments and the local subgraph of the molecular graph enables fragments
to be placed efficiently onto the molecular graph. Further optimization is
achieved by placing similar fragments into bins using a hashing scheme based
on the canonical numbering. The graph perception algorithm is illustrated in
detail. |
|
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Barakat MT, Dean PM. |
J Comput Aided Mol Des. 1995
Aug;9(4):341-50. |
This paper is the first of a
series which examines the problems of atom assignment in automated de novo
drug design. In subsequent papers, a combinatoric optimization method for
fragment placement onto 3D molecular graphs is provided. Molecules are built
from molecular graphs by placing fragments onto the graph. Here we examine
the transferability of atomic residual charge, by fragment placement, with
respect to the electrostatic potential. This transferability has been tested
on 478 molecular structures extracted from the Cambridge Structural Database.
The correlation found between the electrostatic potential computed from
composite fragments and that computed for the whole molecule was encouraging,
except for extended conjugated systems. |
|
|
Barker J, Courtney S,
Hesterkamp T, Ullmann D, Whittaker M |
Exp Opin Drug Discov. 2006
1, 225-236 |
Fragment screening by
biochemical assay. |
[No abstract] |
|
Bartoli S, Fincham CI,
Fattori D. |
Curr Opin Drug Discov Devel.
2007 Jul;10(4):422-9. |
Fragment-based
drug design: combining philosophy with technology. |
Fragment-based drug design
began more than ten years ago and has been steadily gaining in popularity.
This review discusses how fragments have been used to choose druggable
targets, and what parameters need to be evaluated if a fragment hit is to be
considered a suitable ligand for development. Examples of fragment-based
screening from the recent literature are reviewed to highlight the various
approaches used, along with the possible application of additional techniques
to fragment screening against immobilized targets. Finally, mention is made
of two different areas, multi-target drug discovery and selective tumor cell
targeting, where fragment-based approaches may play an important role in the
future. |
|
Baurin N, Aboul-Ela F,
Barril X, Davis B, Drysdale M, Dymock B, Finch H, Fromont C, Richardson C,
Simmonite H, Hubbard RE. |
J Chem Inf Comput Sci. 2004
Nov-Dec;44(6):2157-66. |
We have designed four
generations of a low molecular weight fragment library for use in NMR-based
screening against protein targets. The library initially contained 723
fragments which were selected manually from the Available Chemicals
Directory. A series of in silico filters and property calculations were
developed to automate the selection process, allowing a larger database of
1.79 M available compounds to be searched for a further 357 compounds that
were added to the library. A kinase binding pharmacophore was then derived to
select 174 kinase-focused fragments. Finally, an additional 61 fragments were
selected to increase the number of different pharmacophores represented
within the library. All of the fragments added to the library passed quality
checks to ensure they were suitable for the screening protocol, with
appropriate solubility, purity, chemical stability, and unambiguous NMR
spectrum. The successive generations of libraries have been characterized
through analysis of structural properties (molecular weight, lipophilicity,
polar surface area, number of rotatable bonds, and hydrogen-bonding
potential) and by analyzing their pharmacophoric complexity. These
calculations have been used to compare the fragment libraries with a
drug-like reference set of compounds and a set of molecules that bind to
protein active sites. In addition, an analysis of the overall results of
screening the library against the ATP binding site of two protein targets
(HSP90 and CDK2) reveals different patterns of fragment binding,
demonstrating that the approach can find selective compounds that
discriminate between related binding sites. |
|
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Baurin N, Baker R,
Richardson C, Chen I, Foloppe N, Potter A, Jordan A, Roughley S, Parratt M,
Greaney P, Morley D, Hubbard RE. |
J Chem Inf Comput Sci. 2004
Mar-Apr;44(2):643-51. |
We have implemented five
drug-like filters, based on 1D and 2D molecular descriptors, and applied them
to characterize the drug-like properties of commercially available chemical
compounds. In addition to previously published filters (Lipinski and Veber),
we implemented a filter for medicinal chemistry tractability based on lists
of chemical features drawn up by a panel of medicinal chemists. A filter
based on the modeling of aqueous solubility (>1 microM) was derived in-house,
as well as another based on the modeling of Caco-2 passive membrane
permeability (>10 nm/s). A library of 2.7 million compounds was collated
from the 23 compound suppliers and analyzed with these filters, highlighting
a tendency toward highly lipophilic compounds. The library contains 1.6 M
unique structures, of which 37% (607,223) passed all five drug-like filters.
None of the 23 suppliers provides all the members of the drug-like subset,
emphasizing the benefit of considering compounds from various compound
suppliers as a source of diversity for drug discovery. |
|
|
Baurin N, Mozziconacci JC,
Arnoult E, Chavatte P, Marot C, Morin-Allory L. |
J Chem Inf Comput Sci. 2004
Jan-Feb;44(1):276-85. |
Using classification (SOM,
LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN,
Linear), this paper details the building of eight 2D-QSAR models from a 266
COX-2 inhibitor training set. The predictive performances of these eight
models were subsequently compared using an 88 COX-2 inhibitor test set. Each
ligand is described by 52 2D descriptors expressed as van der Waals Surface
Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models
is the neural network model (BRANN), which is able to select a subset, from
the 88 ligand test set, that contains 94% COX-2 active inhibitors
(pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR
consensus prediction protocol that is shown to be more predictive than any
single QSAR model: our C3 consensus approach is able to select a subset from
the 88 ligand test set that contains 94% active inhibitors and 83% of all the
actives. The 2D QSAR consensus protocol was finally applied to the
high-throughput virtual screening of the NCI database, containing 193,477
organic compounds. |
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Baurin N, Vangrevelinghe E,
Morin-Allory L, Merour JY, Renard P, Payard M, Guillaumet G, Marot C. |
J Med Chem. 2000 Mar
23;43(6):1109-22. |
Displaying an unprecedented
structural diversity, 119 I(2) ligands, and their pK(i) values, were
collected and submitted to a comparative molecular fields analysis (CoMFA)
study. They were discerned into three structural subsets (A, B, C), to
explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more
complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA
methology were explored. The applied method used two pharmacophore templates
and seven molecular field combinations (electrostatic, lipophilic, steric),
as well as eight alignment methods (two point-by-point and six
similarity-based variations). That way, 644 CoMFA models were obtained and
further selected according to their predictive ability through two filters.
The first filter was mainly based on the q(2), which internally evaluates the
predictive ability from the training set. For the second filter, the
predictive ability was externally evaluated through the prediction of test
sets. Finally, one model was extracted from the whole data as the best.
Indeed, it combines three features of upmost importance for the further
design of ligands endowed with high I(2) affinity: structural diversity (n =
73), robustness (N = 9, r(2) = 0.96, s = 0. 28, F = 148), and a great fully
assessed predictive ability (q(2) = 0.50, r(2)(test set) = 0.81, n(test set)
= 46). On the basis of structural data and CoMFA isocontours, some elements
of the I(2) tridimensional pharmacophore are also suggested. |
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Bender A, Mussa HY, Glen RC. |
J Biomol Screen. 2005
Oct;10(7):658-66. Epub 2005 Sep 16. |
A fragment-based similarity
searching method, MOLPRINT 2D, was employed for virtual screening of
Escherichia coli dihydrofolate reductase inhibitors. Using the original
training set of 50,000 compounds, only marginal enrichment factors (between 1
and 3) could be achieved on the test library. The active structures contained
in the training and test libraries represented different types of "chemistry",
that is, different substructural features associated with activity. Training
and test sets were pooled in a 2nd step and randomly split into training and
test of equal size, with the objective of smoothing out the different
chemical characteristics of both libraries. In a 10-fold cross-validation
study on the new training and test sets, typically 10-fold enrichment could
be found in the first 96 positions, 4-fold enrichment in the first 384
positions, and 3-fold enrichment in the first 1536 positions, corresponding
to 6, 10, and 28 hits, respectively (out of a total of 307; activity defined
as average residual activity of less than 80%). The conclusions are 2-fold.
On one hand, the exact fragment-matching similarity searching method employed
here is not capable of finding completely novel hit structures. On the other
hand, this study emphasizes the requirement for a comparable distribution of
chemical features of the training and test sets. MOLPRINT 2D is freely
downloadable from http://www.cheminformatics.org. |
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|
Blume A, Angulo J, Biet T,
Peters H, Benie AJ, Palcic M, Peters T. |
J Biol Chem. 2006 Oct
27;281(43):32728-40. Epub 2006 Aug 21. |
Saturation transfer
difference NMR experiments on human blood group B alpha-(1,3)-galactosyltransferase
(GTB) for the first time provide a comprehensive set of binding epitopes of
donor substrate analogs in relation to the natural donor UDP-Gal. This study
revealed that the enzyme binds several UDP-activated sugars, including
UDP-Glc, UDP-GlcNAc, and UDP-GalNAc. In all cases, UDP is the dominant
binding epitope. To identify the minimum requirements for specific binding, a
detailed analysis utilizing a fragment-based approach was employed. The
binding of donor substrate to GTB is essentially controlled by the base as a
"molecular anchor." Uracil represents the smallest fragment that is
recognized, whereas CDP, AMP, and GDP do not exhibit any significant binding
affinity for the enzyme. The ribose and beta-phosphate moieties increase the
affinity of the ligands, whereas the pyranose sugar apparently weakens the
binding, although this part of the molecule controls the specificity of the
enzyme. Accordingly, UDP represents the best binder. The binding affinities
of UDP-Gal, UDP-Glc, and UMP are about the same, but lower than that of UDP.
Furthermore, we observed that beta-D-galactose and alpha-D-galactose bind
weakly to GTB. Whereas beta-D-galactose binds to the acceptor and donor
sites, it is suggested that alpha-D-galactose occupies a third hitherto
unknown binding pocket. Finally, our experiments revealed that modulation of
enzymatic activity by metal ions critically depends on the total enzyme
concentration, raising the question as to which of the bivalent metal cations
Mg(2+) and Mn(2+) is more relevant under physiological conditions. |
|
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Blume A, Benie AJ, Stolz F,
Schmidt RR, Reutter W, Hinderlich S, Peters T. |
J Biol Chem. 2004 Dec
31;279(53):55715-21. Epub 2004 Oct 21. |
The bifunctional enzyme
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is the key
enzyme for the biosynthesis of sialic acids. As terminal components of
glycoconjugates, sialic acids are associated with a variety of pathological
processes such as inflammation and cancer. For the first time, this study
reveals characteristics of the interaction of the epimerase site of the
enzyme with its natural substrate, UDP-N-acetylglucosamine (UDP-GlcNAc) and
derivatives thereof at atomic resolution. Saturation transfer difference NMR
experiments were crucial in obtaining ligand binding epitopes and to rank
ligands according to their binding affinities. Employing a fragment based
approach, it was possible to assign the major component of substrate
recognition to the UDP moiety. In particular, the binding epitopes of the
uridine moieties of UMP, UDP, UDP-GalNAc, and UDP-GlcNAc are rather similar,
suggesting that the binding mode of the UDP moiety is the same in all cases.
In contrast, the hexopyranose units of UDP-GlcNAc and UDP-GalNAc display
small differences reflecting the inability of the enzyme to process
UDP-GalNAc. Surprisingly, saturation transfer difference NMR titrations show
that UDP has the largest binding affinity to the epimerase site and that at
least one phosphate group is required for binding. Consequently, this study
provides important new data for rational drug design. |
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|
Blundell TL, Sibanda BL,
Montalvao RW, Brewerton S, Chelliah V, Worth CL, Harmer NJ, Davies O, Burke
D. |
Philos Trans R Soc Lond B
Biol Sci. 2006 Mar 29;361(1467):413-23. Review. |
Impressive progress in
genome sequencing, protein expression and high-throughput crystallography and
NMR has radically transformed the opportunities to use protein
three-dimensional structures to accelerate drug discovery, but the quantity
and complexity of the data have ensured a central place for informatics.
Structural biology and bioinformatics have assisted in lead optimization and
target identification where they have well established roles; they can now
contribute to lead discovery, exploiting high-throughput methods of structure
determination that provide powerful approaches to screening of fragment
binding. |
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|
Braisted AC, Oslob JD,
Delano WL, Hyde J, McDowell RS, Waal N, Yu C, Arkin MR, Raimundo BC. |
J Am Chem Soc. 2003 Apr
2;125(13):3714-5. No abstract available. |
Discovery
of a potent small molecule IL-2 inhibitor through fragment assembly. |
Using a site-directed
fragment discovery method called tethering, we have identified a 60 nM small
molecule antagonist of a cytokine/receptor interaction (IL-2/IL2R) with
cell-based activity. Starting with a low micromolar hit, we employed a
combination of tethering, structural biology, and computational analysis to
design a focused set of 20 compounds. Eight of these compounds were at least
5-fold more active than the original hit. One of these compounds showed a
50-fold enhancement and represents the highest affinity inhibitor reported
against this protein-protein target class. This method of coupling selected
fragments with a low micromolar hit shows great potential for generating
high-affinity lead compounds. |
|
Bright J. |
IDrugs. 2007
May;10(5):308-9. No abstract available. |
[No abstract] |
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|
Capdeville R, Buchdunger E,
Zimmermann J, Matter A. |
Nat Rev Drug Discov. 2002
Jul;1(7):493-502. Review. |
Glivec
(STI571, imatinib), a rationally developed, targeted anticancer drug. |
In the early 1980s, it
became apparent that the work of pioneers such as Robert Weinberg, Mariano
Barbacid and many others in identifying cancer-causing genes in humans was
opening the door to a new era in anticancer research. Motivated by this, and
by dissatisfaction with the limited efficacy and tolerability of available
anticancer modalities, a drug discovery programme was initiated with the aim
of rationally developing targeted anticancer therapies. Here, we describe how
this programme led to the discovery and continuing development of Glivec
(Gleevec in the United States), the first selective tyrosine-kinase inhibitor
to be approved for the treatment of a cancer. |
|
Card GL, Blasdel L, England
BP, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim PN, Artis DR, Bollag G,
Milburn MV, Kim SH, Schlessinger J, Zhang KY. |
Nat Biotechnol. 2005
Feb;23(2):201-7. Epub 2005 Jan 30. |
Cyclic nucleotide
phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a
variety of cellular processes. We describe a family of potent PDE4 inhibitors
discovered using an efficient method for scaffold-based drug design. This method
involves an iterative approach starting with low-affinity screening of
compounds followed by high-throughput cocrystallography to reveal the
molecular basis underlying the activity of the newly identified compounds.
Through detailed structural analysis of the interaction of the initially
discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray
crystallography, we identified three sites of chemical substitution and
designed small selective libraries of scaffold derivatives with modifications
at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor
was achieved after only two rounds of chemical synthesis and the structural
analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the
robustness of this approach for identifying new inhibitors that can be
further developed into drug candidates. |
|
|
Carr RA, Congreve M, Murray
CW, Rees DC. |
Drug Discov Today. 2005 Jul
15;10(14):987-92. Review. |
Fragment-based lead
discovery (also referred to as needles, shapes, binding elements, seed
templates or scaffolds) is a new lead discovery approach in which much lower
molecular weight (120-250 Da) compounds are screened relative to HTS
campaigns. Fragment-based hits are typically weak inhibitors (10 microM-mM),
and therefore need to be screened at higher concentration using very
sensitive biophysical detection techniques such as protein crystallography
and NMR as the primary screening techniques, rather than bioassays. Compared
with HTS hits, these fragments are simpler, less functionalized compounds
with correspondingly lower affinity. However, fragment hits typically possess
high 'ligand efficiency' (binding affinity per heavy atom) and so are highly
suitable for optimization into clinical candidates with good drug-like
properties. |
|
|
Carter TA, Wodicka LM, Shah
NP, Velasco AM, Fabian MA, Treiber DK, Milanov ZV, Atteridge CE, Biggs WH
3rd, Edeen PT, Floyd M, Ford JM, Grotzfeld RM, Herrgard S, Insko DE, Mehta
SA, Patel HK, Pao W, Sawyers CL, Varmus H, Zarrinkar PP, Lockhart DJ. |
Proc Natl Acad Sci U S A.
2005 Aug 2;102(31):11011-6. Epub 2005 Jul 26. |
Inhibition
of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. |
To realize the full
potential of targeted protein kinase inhibitors for the treatment of cancer,
it is important to address the emergence of drug resistance in treated
patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been
found that confer resistance to the drugs imatinib, gefitinib, and erlotinib.
The mutations weaken or prevent drug binding, and interestingly, one of the
most common sites of mutation in all three kinases is a highly conserved
"gatekeeper" threonine residue near the kinase active site. We have
identified existing clinical compounds that bind and inhibit drug-resistant
mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase
inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and
BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248
potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent
with the clinical efficacy of SU-11248 against imatinib-resistant
gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not
GW-572016 and ZD-6474, potently inhibit the gefitinib- and
erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already
in clinical trials, and our results suggest that they should be considered
for testing in the treatment of gefitinib/erlotinib-resistant non-small cell
lung cancer. The results highlight the strategy of screening existing
clinical compounds against newly identified drug-resistant mutant variants to
find compounds that may serve as starting points for the development of next-generation
drugs, or that could be used directly to treat patients that have acquired
resistance to first-generation targeted therapy. |
|
Caskey CT. |
Annu Rev Med. 2007;58:1-16.
Review. |
Despite advancements in
genetics, chemistry, and protein engineering, recent years have seen fewer
approvals of new drugs, increases in development costs, and high-profile drug
withdrawals. This article focuses on technologic methods for improving drug
development efficiency. These technologies include high-content cell
screening, expression profiling, mass spectroscopy, mouse models of disease,
and a post-launch screening program that enables investigations of adverse
drug effects. Implementation of these new technologies promises to improve
performance in drug development and safety. |
|
|
Chau PL, Dean PM. |
J Comput Aided Mol Des. 1994
Oct;8(5):527-44. |
Electrostatic
complementarity between proteins and ligands. 2. Ligand moieties. |
Drug design strategies consider
factors governing intermolecular interactions to build up putative ligands.
In many strategies, the ligand is constructed using fragments which are
placed in the site sequentially. The optimization is then performed with each
fragment. We would like to examine if this optimization strategy could
generate ligands with optimal electrostatic interactions. The electrostatic
complementarities between constituent moieties and the receptor site have
been calculated. The whole-ligand complementarity does not appear to be the
mathematical mean of the individual complementarities, nor have we found a
simple relationship between the moiety and whole-ligand complementarities.
The results demonstrate clearly that, using a simple model, it is very
difficult to predict the electrostatic potential complementarity of the whole
ligand from the complementarities of its constituent chemical moieties. This
means that ligand design strategies must optimize the electrostatic
complementarity globally, and not moiety by moiety. |
|
Chau PL, Dean PM. |
J Comput Aided Mol Des. 1992
Aug;6(4):407-26. |
Department of Pharmacology,
University of Cambridge, U.K. |
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Chau PL, Dean PM. |
J Comput Aided Mol Des. 1992
Aug;6(4):397-406. |
In this paper a database of
small frequently occurring molecular fragments is used for the determination
of fragment bond lengths from the Cambridge Structural Database. A large
number of bond types are described that have not been reported previously. |
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Chau PL, Dean PM. |
J Comput Aided Mol Des. 1992
Aug;6(4):385-96. |
If a method is to be
developed to assemble putative ligand structures in site-directed drug
design, from molecular graphs generated in the site, then basic building
blocks are needed. Structure assembly is a combinatoric process that needs to
be optimised if it is to be tractable. What has to be determined is whether
small molecular fragments can have transferable properties from one molecule
to another. In this paper we determine all possible combinations of 3-, 4-
and 5-atom aliphatic fragments from a small set of atoms H, C, N, O, F or Cl.
The frequency of occurrence of these candidate fragments is searched for in
the Cambridge Structural Database. A similar analysis is performed on charged
fragments. A more restricted search is carried out for P and S and aromatic
structures. A basic set of fragments can be derived that have a significant
frequency in known crystal structures. The transferability of fragment
properties is discussed in subsequent papers. |
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Chavatte P, Yous S, Marot C,
Baurin N, Lesieur D. |
J Med Chem. 2001 Sep
27;44(20):3223-30. |
The three-dimensional
quantitative structure-activity relationship (3D-QSAR) approach using
comparative molecular field analysis (CoMFA) was applied to an extensive
series of 305 varied diarylheterocyclic derivatives known as COX-2 selective
inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective
COX-2 inhibitor, was used to derive the putative bioactive conformation of
these inhibitors. Five statistically significant models were obtained from
the randomly constituted training sets (229 compounds) and subsequently
validated with the corresponding test sets (76 compounds). The best
predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F =
261.545) was selected for further comparison of the CoMFA contour maps
obtained for steric, electrostatic, and lipophilic fields with the enzyme
structure. The high level of compatibility with the COX-2 enzyme topology
shows the great accuracy of this model that can predict inhibitory activities
for a wide range of compounds and offers important structural insight into
designing novel antiinflammatory drugs prior to their synthesis. |
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Chen J, Zhang Z, Stebbins
JL, Zhang X, Hoffman R, Moore A, Pellecchia M. |
ACS Chem Biol. 2007 May
22;2(5):329-36. Epub 2007 Apr 27. |
A
fragment-based approach for the discovery of isoform-specific p38alpha
inhibitors. |
In this study, we describe a
novel approach for lead discovery against protein kinases, pharmacophore by
interligand nuclear Overhauser effect (ILOE), in which a pair of ligands that
bind to adjacent pockets on the target surface is identified by the detection
of protein-mediated ILOEs. We demonstrate that a pharmacophore-based search
guided by experimental binding data of weakly interacting fragments can be
rapidly and efficiently used to identify (or synthesize) high-affinity,
selective ligands. Targeting the inactive state of protein kinases represents
a promising approach to achieve selectivity and cellular efficacy. In this
respect, when we apply the method for the discovery of potent p38alpha
inhibitors, we also demonstrate that the resulting bidentate compounds are highly
selective and exhibit a cellular activity that parallels their in vitro
binding to the inactive form of the kinase. The method is relatively simple
and of general applicability, and as such we anticipate its potential
implementation against a variety of macromolecular targets, including not
only protein kinases but also those involved in protein-protein interactions
or even nucleic acids. |
|
Chen X, Reynolds CH. |
J Chem Inf Comput Sci. 2002
Nov-Dec;42(6):1407-14. |
2D fragment-based similarity
searching is one of the most popular techniques for searching a large
database of chemical structures and has been widely applied in drug
discovery. However, its performance, especially its effectiveness in
retrieving active structural analogues, has not been adequately studied. We
report a series of computational experiments, where we systematically studied
the influence of structural descriptors and similarity coefficients on the
effectiveness of similarity searching. The study was conducted using two
public large data sets, NCI anti-AIDS and MDDR. Four sets of 2D linear
fragment descriptors, based on the original definitions of atom pairs and
atom sequences, were compared. The effect of using the Tanimoto coefficient
and the Euclidean distance was studied as a function of descriptor set. The
results clearly indicate that the Tanimoto coefficient is superior to the
Euclidean distance in 2D-fragment based similarity searching, in terms of hit
rate, while atom sequences demonstrate the best overall performance among the
structural descriptors we studied. |
|
|
Cherry M, Williams DH. |
Curr Med Chem. 2004
Mar;11(6):663-73. Review. |
Recent years have seen an
explosion in the number of publicly available x-ray crystal structures of
protein kinases. These structures have provided a wealth of information on
the regulatory mechanisms, conformational plasticity and drugability of this
important family of enzymes. Drawing upon structural information, new
insights into the development of protein kinase inhibitors are discussed
including de-novo design, molecular templates for ATP competitive inhibitors
and alternative mechanisms of inhibition. The highly conserved nature of the
ATP binding site is of central concern to drug development and the concept of
a selectivity profile has arisen with structure-based design emerging as a
key tool for addressing the challenges of specificity. In addition,
protein-ligand complexes, where the enzyme is in an inactive conformation,
signify an alternate approach to protein kinase inhibition. The belief that
an inactive kinase presents a less conserved target is reviewed using
observations on the structural changes occurring during protein kinase
regulation. |
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|
Choong IC, Lew W, Lee D,
Pham P, Burdett MT, Lam JW, Wiesmann C, Luong TN, Fahr B, DeLano WL, McDowell
RS, Allen DA, Erlanson DA, Gordon EM, O'Brien T. |
J Med Chem. 2002 Nov
7;45(23):5005-22. |
The design, synthesis, and
in vitro activities of a series of potent and selective small-molecule
inhibitors of caspase-3 are described. From extended tethering, a salicylic
acid fragment was identified as having binding affinity for the S(4) pocket
of caspase-3. X-ray crystallography and molecular modeling of the initial
tethering hit resulted in the synthesis of 4, which reversibly inhibited
caspase-3 with a K(i) = 40 nM. Further optimization led to the identification
of a series of potent and selective inhibitors with K(i) values in the 20-50
nM range. One of the most potent compounds in this series, 66b, inhibited
caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs
a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal
structure of 4 and 66b supports the predicted binding modes of our compounds
with caspase-3. |
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Ciulli A, Lobley CM, Tuck
KL, Smith AG, Blundell TL, Abell C. |
Acta Crystallogr D Biol
Crystallogr. 2007 Feb;63(Pt 2):171-8. Epub 2007 Jan 16. |
The crystal structure of
Escherichia coli ketopantoate reductase in complex with
2'-monophosphoadenosine 5'-diphosphoribose, a fragment of NADP+ that lacks
the nicotinamide ring, is reported. The ligand is bound at the enzyme active
site in the opposite orientation to that observed for NADP+, with the adenine
ring occupying the lipophilic nicotinamide pocket. Isothermal titration
calorimetry with R31A and N98A mutants of the enzyme is used to show that the
unusual ;reversed binding mode' observed in the crystal is triggered by
changes in the protonation of binding groups at low pH. This research has
important implications for fragment-based approaches to drug design, namely
that the crystallization conditions and the chemical modification of ligands
can have unexpected effects on the binding modes. |
|
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Ciulli A, Williams G, Smith
AG, Blundell TL, Abell C. |
J Med Chem. 2006 Aug 10;49(16):4992-5000. |
Mapping interactions at
protein-ligand binding sites is an important aspect of understanding many
biological reactions and a key part of drug design. In this paper, we have
used a fragment-based approach to probe "hot spots" at the
cofactor-binding site of a model dehydrogenase, Escherichia coli ketopantoate
reductase. Our strategy involved the breaking down of NADPH (Kd = 300 nM)
into smaller fragments and the biophysical characterization of their binding
using WaterLOGSY NMR spectroscopy, isothermal titration calorimetry (ITC),
and inhibition studies. The weak binding affinities of fragments were
measured by direct ITC titrations under low c value conditions. The
2'-phosphate and the reduced nicotinamide groups were found to contribute a
large part of the binding energy. A combination of ITC and site-directed
mutagenesis enabled us to locate the fragments at separate hot spots on
opposite ends of the cofactor-binding site. This study has identified
structural determinants for cofactor recognition that represent a blueprint
for future inhibitor design. |
|
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Clark M, Guarnieri F,
Shkurko I, Wiseman J. |
J Chem Inf Model. 2006
Jan-Feb;46(1):231-42. |
Grand
canonical Monte Carlo simulation of ligand-protein binding. |
A new application of the
grand canonical thermodynamics ensemble to compute ligand-protein binding is
described. The described method is sufficiently rapid that it is practical to
compute ligand-protein binding free energies for a large number of poses over
the entire protein surface, thus identifying multiple putative ligand binding
sites. In addition, the method computes binding free energies for a large number
of poses. The method is demonstrated by the simulation of two protein-ligand
systems, thermolysin and T4 lysozyme, for which there is extensive
thermodynamic and crystallographic data for the binding of small, rigid
ligands. These low-molecular-weight ligands correspond to the molecular
fragments used in computational fragment-based drug design. The simulations
correctly identified the experimental binding poses and rank ordered the
affinities of ligands in each of these systems. |
|
Coles M, Heller M, Kessler
H. |
Drug Discov Today. 2003 Sep
1;8(17):803-10. Review. |
NMR-based ligand screening
is now an established field in its own right. In recent years, advances in
both methodology and hardware have broadened its range of applications and
pushed back practical limitations, leading to the growing importance of NMR
screening as a tool in industrial drug research. An overview of new screening
methods and applications is presented here, and ways in which NMR-screening
is being used in cooperation with other screening techniques are discussed. |
|
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Congreve M, Aharony D,
Albert J, Callaghan O, Campbell J, Carr RA, Chessari G, Cowan S, Edwards PD,
Frederickson M, McMenamin R, Murray CW, Patel S, Wallis N. |
J Med Chem. 2007 Mar
22;50(6):1124-32. Epub 2007 Feb 22. |
Fragment-based lead
discovery has been successfully applied to the aspartyl protease enzyme
beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif
binding to the two catalytic aspartic acid residues in the active site of the
enzyme were the chemical starting points. Structure-based design approaches
have led to identification of low micromolar lead compounds that retain these
interactions and additionally occupy adjacent hydrophobic pockets of the
active site. These leads form two subseries, for which compounds 4 (IC50 = 25
microM) and 6c (IC50 = 24 microM) are representative. In the latter series,
further optimization has led to 8a (IC50 = 690 nM). |
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Congreve M, Carr R, Murray
C, Jhoti H. |
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