A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition

Article abstract of DOI:10.1002/cmdc.201800193

A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a K_d value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.

Full text of DOI:10.1002/cmdc.201800193

DOI: 10.1002/cmdc.201800193
Communications
A DNA-Encoded Library of Chemical Compounds Based on
Common Scaffolding Structures Reveals the Impact of
Ligand Geometry on Protein Recognition
Nicholas Favalli,[a] Stefan Biendl,[a] Marco Hartmann,[a] Jacopo Piazzi,[b] Filippo Sladojevich,[c]
Susanne Grꢀslund,[d, e] Peter J. Brown,[d] Katja Nꢀreoja,[e] Herwig Schꢁler,[e]
Jçrg Scheuermann,[a] Raphael Franzini,*[a, f] and Dario Neri*[a]
A DNA-encoded chemical library (DECL) with 1.2 million com-
pounds was synthesized by combinatorial reaction of seven
central scaffolds with two sets of 343ꢂ492 building blocks. Li-
brary screening by affinity capture revealed that for some
target proteins, the chemical nature of building blocks domi-
nated the selection results, whereas for other proteins, the
central scaffold also crucially contributed to ligand affinity. Mol-
ecules based on a 3,5-bis(aminomethyl)benzoic acid core struc-
ture were found to bind human serum albumin with a Kd value
of 6 nm, while compounds with the same substituents on an
equidistant but flexible l-lysine scaffold showed 140-fold lower
affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking
moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-
proline showed no detectable binding to the target. This work
suggests that central scaffolds which predispose the orienta-
tion of chemical building blocks toward the protein target may
enhance the screening productivity of encoded libraries.
chemical libraries depends not only on the number and char-
acteristics of the building blocks used for library construction,
but also on library design.[1] We previously reported a DNA-en-
coded chemical library based on a conserved (S)-2,3-diamino-
propanoic acid scaffold, which had been combinatorially react-
ed with two sets of carboxylic acids that yielded nanomolar
binders against various target proteins, including serum albu-
mins and tankyrase-1.[2] These results motivated us to investi-
gate how the geometry, stereochemistry, and rigidity of a cen-
tral scaffold influences the outcome of screening results and
the binding affinity of selected compounds.[3] Herein we de-
scribe the synthesis and characterization of a DNA-encoded
chemical library[4] obtained by the combinatorial modification
of seven central scaffolds, each bearing both an amine and an
azide moiety. The use of these orthogonal coupling sites for
two diverse sets of building blocks (343 and 492 building
blocks, respectively), eventually yielded a library with an overall
size of 1.2 million compounds. Affinity measurements per-
formed on selected hit compounds indicate that, for certain
targets, the geometry and rigidity of the central scaffold can
have a strong impact on the dissociation constants of the cor-
responding ligands.[5]
The encoding of compounds with DNA tags, serving as amplifi-
able identification barcodes, allows the facile construction and
screening of large combinatorial chemical libraries.[1] The suc-
cessful identification of binding molecules from DNA-encoded
In this study, we explored whether subtle chemical variations
of the central molecular “scaffold” impact the affinity and spe-
cificity of the discovered protein ligands. For this reason, we
coupled seven trifunctional carboxylic acid derivatives to oligo-
nucleotides, to enable the subsequent coupling and encoding
of two sets of building blocks, resulting in a combinatorial li-
brary of 7ꢂ343ꢂ492=1181292 compounds (Figure 1). The
scaffolds included two stereo-defined protected derivatives of
(R)-2-azido-3-aminopropionic acid (1) and (S)-2-azido-3-amino-
propionic acid (2), the rigidified (2S,4S)-azido-l-proline (5) and
(2S,4R)-azido-l-proline (6), e-azido-d-lysine (3), e-azido-l-lysine
(4) and 3-(aminomethyl)-5-(azidomethyl)benzoic acid (7). The
scaffolds each contained a protected primary amine group and
an azide moiety. Using a split-and-pool protocol,[7] featuring
the reaction of amines with carboxylic acids[8] or the copper(I)-
catalyzed alkyne–azide cycloaddition (CuAAC)[9] of azide deriva-
tives with terminal alkynes, we constructed a library of struc-
turally related compounds. Screening experiments were per-
formed with biotinylated proteins immobilized on streptavidin-
coated magnetic beads.[10] Details of library synthesis and of li-
brary encoding procedures can be found in Supporting Infor-
mation Figure 1.1. Figure 2a shows the results of a library se-
lection performed with biotinylated human serum albumin
[a] N. Favalli, S. Biendl, M. Hartmann, Dr. J. Scheuermann, Prof. Dr. R. Franzini,
Prof. Dr. D. Neri
Institute of Pharmaceutical Sciences, ETH Zꢀrich, Vladimir-Prelog-Weg 4,
8093 Zꢀrich (Switzerland)
E-mail: neri@pharma.ethz.ch
raphael.franzini@utah.edu
[b] Dr. J. Piazzi
Philochem AG, Liebernstrasse 3, 8112 Otelfingen (Switzerland)
[c] Dr. F. Sladojevich
Roche Pharma Research and Early Development, Roche Innovation Center
Basel, F. Hoffmann-La, Roche Ltd., Grenzacherstrasse 124, 4070 Basel (Swit-
zerland)
[d] Dr. S. Grꢁslund, Dr. P. J. Brown
Structural Genomics Consortium (SGC), University of Toronto, Toronto, ON,
M5G 1L7 (Canada)
[e] Dr. S. Grꢁslund, Dr. K. Nꢁreoja, Prof. Dr. H. Schꢀler
Department of Structural Biology, Department of Medical Biochemistry and
Biophysics (MBB), Karolinska Institutet, Scheeles vꢁg 2, 17177 Stockholm
(Sweden)
[f] Prof. Dr. R. Franzini
College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City,
UT 84112 (USA)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cmdc.201800193.
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Figure 1. Representation of the library synthesis scheme. Seven building
blocks (1–7), carrying protected amine functions and azides were coupled to
amino-tagged oligonucleotides, each containing a central sequence
(“code”), which unambiguously identifies the corresponding building block.
After deprotection and using a split-and-pool procedure, carboxylic acids
were coupled to the amines, and the corresponding 343 building blocks “B”
encoded by a ligation procedure. In the final synthesis step the azide moiety
of the central scaffolds was either reacted with terminal alkynes or convert-
ed into a primary amine, allowing the formation of an amide bond with car-
boxylic acids. The final encoding step for building blocks “C” was performed
using partially complementary oligonucleotides and Klenow polymerization,
as described.[6]
(HSA), followed by high-throughput sequencing for the iden-
tification and relative quantification of the DNA barcodes.[10]
These selection results are displayed in pseudo-four-dimen-
sional space, using three dimensions for definition of the iden-
tity of the three sets of building blocks (codes A, B and C),
while spheres of different colors represent the fourth dimen-
sion (corresponding to the number of sequence counts for in-
dividual compounds) above a threshold of 3000 counts. The
plot indicates that the most highly enriched library members
all contained the 3,5-bis(aminomethyl)benzoic acid scaffold
(code A=7), whereas there was no such preference in the pre-
selected library and selections with a set of control proteins
used in our laboratory (Supporting Information Figures 6.2 and
6.3). Figure 2b presents a graphical display of the selection
counts for the library members, arranged with seven code A
structures on the x-axis and the 343ꢂ492=168756 combina-
tions of code B and code C on the y-axis. Compound A7/B66/
C292 is the most enriched compound (Figure 2). The com-
pound consisted of the 3,4-di(aminomethyl)benzoic acid scaf-
fold, with 3-(3,4,5-trimethoxyphenyl)propanoic acid (B66), and
2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (C292). The
same 3-(3,4,5-trimethoxyphenyl)propanoic acid found as build-
ing block B66 in the second reaction cycle position of com-
pound A7/B66/C292, was also found in another combination.
In particular the 3-(3,4,5-trimethoxyphenyl)propanoic acid
moiety was found as building block C56 in the third reaction
cycle position of a second highly enriched combination (A7/
B329/C56). In a different representation of selection results,
keeping code B constant (i.e., restricting the analysis to com-
pounds based on the B66 building block), the preferential en-
Figure 2. Results of library selections against human serum albumin (HSA).
a) Selection fingerprint. The individual library members are unambiguously
identified by their codes A (ranging between 1 and 7), B (ranging between 1
and 343) and C (ranging between 1 and 492). The number of sequence
counts for each compound is displayed as spheres of a different color, with
a cutoff threshold set at 3000 counts. b) The code A analysis shows how the
different scaffolds (code A, ranging between 1 and 7) display different en-
richment factors for each building block A and B combination (Code BꢂCo-
de C, ranging between 1 and 1.7ꢂ105). c) Selection fingerprint obtained
fixing the code B=66 (corresponding to 3-(3,4,5-trimethoxyphenyl)propano-
ic acid) with variable codes A (ranging between 1 and 7) and C (ranging be-
tween 1 and 492). This analysis shows A7/B66/C292 as the most enriched
combination of building blocks against HSA. d) Fluorescence polarization
(FP) measurement of FITC conjugates of the most enriched combination of
building blocks (B66/C292), featuring the preferred scaffold A7 (red and
blue curves) or scaffolds A4 (green) and A6 (orange). A FITC conjugate of
A7/B66/C292 was also tested against bovine serum albumin (BSA) and re-
vealed a double-digit micromolar dissociation constant (Kd) against that pro-
tein (red curve). The acetylated PEG-fluorescein derivative showed no de-
tectable binding to HSA (pink curve).
richment of library members based on the A7 scaffold (and of
the A7/B66/C292 in particular) is visible (Figure 2c). The disso-
ciation constant (Kd) of a fluorescein derivative of A7/B66/
C292 determined by concentration-dependent fluorescence
polarization experiments was found to be 7 nm. In contrast, ex-
changing the A7 scaffold by two alternative diamines drastical-
ly decreased the affinity for HSA, in agreement with the selec-
tion results (Kd(A4/B66/C292)=1.6 mm, Kd(A6/B66/C292)=
1.2 mm). The fluorophore-labeled and acetylated PEG2-diamino
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Figure 3. Binding properties of compound A7/B66/C292 analyzed by surface plasmon resonance (SPR) against HSA immobilized on a BIAcore chip (CM5,
5770 RU). a) SPR profile of compound R-(A7/B66/C292) at various concentrations (5 mm, 1.25 mm, 312 nm, 78.1 nm, 19.5 nm). An overall fitting of the resulting
curves (4.7 mm, 2.3 mm, 1.2 mm, and 582 nm) revealed a koff =7.4ꢂ10À3 sÀ1 and a kon =2.0ꢂ105 sÀ1 mÀ1, resulting in a Kd =36.6 nm b) SPR profile of compound
R-(A6/B66/C292) at different concentrations (5 mm, 1.25 mm, 312 nm, 78.1 nm, 19.5 nm). c) SPR profile of compound R-(A4/B66/C292) at different concentra-
tions (5 mm, 1.25 mm, 312 nm, 78.1 nm, 19.5 nm).
linker exhibited a residual dissociation constant higher than
100 mm (Figure 2d).
We confirmed the fluorescence polarization findings by
studying the interaction of compounds A7/B66/C292, A6/B66/
C292 and A4/B66/C292 with HSA using surface plasmon reso-
nance on a BIAcore instrument. Figure 3 shows that compound
A7/B66/C292 bound to its cognate target with a kinetic disso-
ciation constant (koff) of 4.5ꢂ10À3 sÀ1. In contrast, the structural
analogues featuring l-lysine and (2S,4R)-amino-l-proline as a
central scaffold did not bind to HSA under the same experi-
mental conditions (Figure 3), confirming the role played by the
A7 3,5-bis(aminomethyl)benzoic acid core structure.
Library selections performed for human tankyrase-1 (TNKS1)
revealed a distinctive pattern of enriched compounds, featur-
ing a preference for linker A4 (l-lysine) and building block
B101 (thymine-1-acetic acid) (Figure 4a). The observed finger-
print was observed when selections were performed at various
concentrations of Tween 20, providing confidence about the
reproducibility of the screening procedure[1h] (Supporting Infor-
mation Figure 6.1). A plot of selection results, emphasizing se-
quence counts for various library members featuring the B101
building block, highlighted the preferential enrichment of
compounds with linker A4 and with certain conserved struc-
tural features of C building blocks (Figure 4b,c). Synthesis of
amide derivatives the most enriched compound A4/B101/
C491 revealed a high-affinity binding to the cognate TNKS1
protein immobilized on a BIAcore chip (Kd =15Æ8 nm), while
the use of d-lysine (A3/B101/C491) or of (2S,4S)-amino-l-pro-
line (A5/B101/C491) as linker did not result in any detectable
binding by SPR analysis (Figure 4d–f).
We also explored the impact on affinity constants to TNKS1
for chemical modifications at the site, originally occupied by
the linkage to DNA (Table 1 and Supporting Information
Figure 5.3). While a simple amide derivative exhibited the best
dissociation constant (Kd =15 nm), the corresponding carboxyl-
ic acid or amides derived from 3-aminopropan-1-ol showed a
substantial decrease in binding affinity.
Figure 4. Results of library selections against human tankyrase-1 (TNKS1).
a) Selection fingerprint, revealing a preferential enrichment of compounds
with A4 and B101. b) Plot of sequence counts for library members, featuring
B101 as preferred building block. The plot reveals a preferential enrichment
of library members with linker A4 and building blocks C491, C453, C369,
C183 and C182. The structures of the five most enriched compounds is
shown in panel (c). The BIAcore profiles at various concentrations of ligand
for the amide derivatives of A4/B101/C491, A3/B101/C491, and A5/B101/
C491 are shown in panels (d), (e), and (f). Fitting of the sensorgrams for A4/
B101/C491 in panel (d) yielded a koff =(2.1Æ0.8)ꢂ10À3 sÀ1 and a
When selections were performed with targets for which a
specific building block dominates the ligand enrichment proce-
dure, different fingerprint patterns were observed. Figure 5
k
on =(1.7Æ0.2)ꢂ105 sÀ1 mÀ1, corresponding to a Kd =15Æ8 nm.
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selectivity to other poly(ADP-ribose) polymerases remains to
be established.[15] We anticipate that new DNA-encoded chemi-
cal libraries will be designed in the future, exploiting novel de-
signs for the spatial arrangement of building blocks.
Table 1. Impact of chemical modification at the site of DNA coupling on
dissociation constants.
[b]
Compound ID[a]
R1
R2
Kd
45 (A4/B101/C491)
44 (A4/B101/C458)
54 (A4/B101/183)
46 (A4/B101/C491)
47 (A4/B101/C491)
55 (A4/B101/183)
OH
OH
OH
C491
C458
C183
C491
C491
C183
259 nm
307 nm
258 nm
15 nm
6.0 mm
2.4 mm
Acknowledgements
NH2
NH(CH2)3OH
NH(CH2)3OH
Financial support from the ETH Zꢀrich, the Swiss National Sci-
ence Foundation (Grants 310030B_163479), Sinergia (CRS112_
160699), and from the ERC Advanced Grant “ZAUBERKUGEL”
(Grant agreement 670603) is gratefully acknowledged. The Struc-
tural Genomics Consortium is a registered charity (no. 1097737)
that receives funds from AbbVie, Bayer Pharma AG, Boehringer
Ingelheim, Canada Foundation for Innovation, Eshelman Institute
for Innovation, Genome Canada, Innovative Medicines Initiative
(EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co.,
Novartis Pharma AG, Ontario Ministry of Economic Development
and Innovation, Pfizer, S¼o Paulo Research Foundation-FAPESP,
Takeda, and the Wellcome Trust.
[a] The complete structures are provided in the Supporting Information.
[b] The SPR profiles are shown in Supporting Information Figure 5.3.
shows the results of selections performed against carbonic an-
hydrase IX,
a
tumor-associated cell-surface marker.[11] This
enzyme can by efficiently targeted by ligands containing aro-
matic or heteroaromatic sulfonamides.[12] Indeed, an efficient
enrichment of building blocks B128, B340 and C410 was visi-
ble in the selection fingerprints. In this case, the role of the
central scaffold was less important, as sulfonamide derivatives
for all seven building blocks “A” could be efficiently enriched.
Collectively, the results of this study suggest that the chemi-
cal nature of central scaffolds, defining the orientation and
flexibility of substituents blocks pointing toward the protein
target of interest, may represent an important determinant of
binding affinity. The examples of HSA and TNKS1 binders re-
vealed that subtle differences in the chemical nature of central
scaffolds can lead to substantial variations (i.e., >100-fold dif-
ferences) in binding affinity for the cognate target protein of
interest. The nanomolar binders to HSA and to TNKS1 de-
scribed herein may be useful for serum half-life prolongation
purposes,[13] and the TNKS1 binders as chemical probes for the
biological characterization of TNKS1 function,[14] although the
Conflict of interest
D.N. is a cofounder and shareholder of Philochem AG, and J.S. is
a board member of Philochem AG.
Keywords: bifunctional ligands
libraries · human serum albumin · tankyrase-1
· DNA-encoded chemical
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Manuscript received: March 22, 2018
Accepted manuscript online: && &&, 0000
Version of record online: && &&, 0000
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COMMUNICATIONS
N. Favalli, S. Biendl, M. Hartmann,
J. Piazzi, F. Sladojevich, S. Grꢁslund,
P. J. Brown, K. Nꢁreoja, H. Schꢀler,
J. Scheuermann, R. Franzini,* D. Neri*
Advanced search function: A 1.2-mil-
lion-compound DNA-encoded library
was built on seven central scaffolds
with two sets of 343ꢂ492 building
blocks. Library screening by affinity cap-
ture revealed that for some target pro-
teins, the chemical nature of the build-
ing blocks dominated the selection re-
sults, whereas for other proteins the
central scaffold also crucially contribut-
ed to ligand affinity. This suggests that
predisposing the orientation of chemi-
cal building blocks toward the protein
target may enhance the screening pro-
ductivity of encoded libraries.
&& – &&
A DNA-Encoded Library of Chemical
Compounds Based on Common
Scaffolding Structures Reveals the
Impact of Ligand Geometry on Protein
Recognition
&
ChemMedChem 2018, 13, 1 – 6
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ꢃ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!