Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек
Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On...
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| Published in: | Журнал органічної та фармацевтичної хімії |
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| Date: | 2023 |
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| Pages: | 3-19 |
| ISSN: | 2518-1548 |
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364447878807552 |
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| author | Oksiuta, Oleksandr V. Pashenko, Alexander E. Smalii, Radomyr V. Volochnyuk, Dmitry M. Ryabukhin, Serhii V. |
| author_facet | Oksiuta, Oleksandr V. Pashenko, Alexander E. Smalii, Radomyr V. Volochnyuk, Dmitry M. Ryabukhin, Serhii V. |
| author_institution_txt_mv | [
{
"author": "Oleksandr V. Oksiuta",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Chemspace LLC",
"orcid": ""
},
{
"author": "Alexander E. Pashenko",
"institution": " Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd.; Taras Shevchenko National University of Kyiv",
"orcid": ""
},
{
"author": "Radomyr V. Smalii",
"institution": "Enamine Ltd.",
"orcid": ""
},
{
"author": "Dmitry M. Volochnyuk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd.; Taras Shevchenko National University of Kyiv",
"orcid": ""
},
{
"author": "Serhii V. Ryabukhin",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd.; Taras Shevchenko National University of Kyiv",
"orcid": ""
}
] |
| author_sort | Oksiuta, Oleksandr V. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 19 |
| container_issue | 1 |
| container_start_page | 3 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 21 |
| datestamp_date | 2026-08-23T20:00:17Z |
| description | Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity. |
| doi_str_mv | 10.24959/ophcj.23.275133 |
| first_indexed | 2025-07-23T04:43:15Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Advanced Research
http://ophcj.nuph.edu.ua
UDC 615: 54.057:547.833:577.113
O. V. Oksiuta1,2, A. E. Pashenko1,3,4, R. V. Smalii3, D. M. Volochnyuk1,3,4,
S. V. Ryabukhin1,3,4
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02660 Kyiv, Ukraine
2 Chemspace Ltd., 85 Winston Churchill str., 02094 Kyiv, Ukraine
3 Enamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine
4 Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine
Heterocyclization vs Coupling Reactions:
A DNA-Encoded Libraries Case
Abstract
Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox.
DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-
weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for
every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an
important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present
state and find the ways to improve it.
Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as
from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restric-
tions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual
core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the
most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have
shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.
Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most im-
pactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including
heterocyclizations, have a significant potential to further expand DEL molecular diversity.
Keywords: DNA-encoded libraries technology; orthogonal functional groups; coupling reactions; polyfunctional building
blocks; heterocyclizations; chemoinformatics; scaffold diversity
О. В. Оксюта1,2, A. Є. Пащенко1,3,4, Р. В. Смалій3, Д. М. Волочнюк1,3,4, С. В. Рябухін1,3,4
1 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
2 ТОВ «Кемспейс», вул. Вінстона Черчилля, 85, м. Київ, 02094, Україна
3 НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
4 Київський національний університет імені Тараса Шевченка,
вул. Володимирська, 60, м. Київ, 01033, Україна
Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек
Анотація
Мета. Технології ДНК-кодованих бібліотек (DELT) поступово стають важливою частиною стандартного набору інстру-
ментів для пошуку нових лікарських субстанцій. Наразі DELT прагне знайти своє місце у просторі між класичними
низькомолекулярними кандидатами у ліки з одного боку та високомолекулярними антитілами й пептидами з іншого.
На своєму шляху до подолання «дитячих хвороб», характерних для кожної нової технології, DELT досягли того мо-
менту, коли хімічна різноманітність ДНК-кодованих бібліотек (DEL) стає важливим фактором, на який варто звернути
увагу. У цій статті ми прагнемо ближче розглянути хімічне різноманіття ДНК-кодованих бібліотек у їхньому поточному
стані та знайти можливості для його покращення.
Результати та їх обговорення. Ми визначили DEL-життєздатні будівельні блоки з наявної колекції Enamine Ltd., а також із
віртуальної колекції Chemspace Ltd., використовуючи набір SMARTS, який враховує всі необхідні структурні обмеження.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 4
Журнал органічної та фармацевтичної хімії 2023, 21 (1)
За допомогою таких сучасних інструментів хемоінформатики, як Synt-On, ми проаналізували різноманітність каркасів
як уже синтезованих, так і віртуальних бі- та трифункціональних білдинг-блоків (BB), придатних для реакцій, у яких
ДНК залишається інтактною. Ідентифікація молекулярних скафолдів, використовуваних у нещодавно опублікованих
«on-DNA» реакціях гетероциклізації, та аналіз їх внесення до простору BB, який існує, засвідчили, що нові толерантні
до ДНК гетероциклізації є надзвичайно корисними для розширення хімічної різноманітності в технологіях DEL.
Висновки. Виконаний аналіз дозволив нам визначити, яким функціональним групам варто віддати пріоритет як най-
більш впливовим у процесі дизайну нових BB. Також стало зрозуміло, що розвиток нових толерантних до ДНК реакцій,
зокрема й гетероциклізації, має значний потенціал для подальшого розширення молекулярного різноманіття DEL.
Ключові слова: технологія ДНК-кодованих бібліотек; ортогональні функціональні групи; реакції каплінгу; поліфункціо-
нальні білдинг-блоки; гетероциклізації; хемоінформатика; разноманітність молекулярних каркасів
Citation: Oksiuta, O. V.; Pashenko, A. E.; Smalii, R. V.; Volochnyuk, D. M.; Ryabukhin, S. V. Heterocyclization vs Coupling Reactions:
A DNA-Encoded Libraries Case. Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1), 3 – 19.
https://doi.org/10.24959/ophcj.23.275133
Supporting information: The links to source databases: Enamine Ltd. DEL-viable stock bi- and tri-functional core building blocks
(freely available at https://cloud.chem-space.com/s/zk7QraSYsrcn7c4); ChemSpace tangible virtual DEL-viable bi- and tri-functional
core building blocks (freely available at https://cloud.chem-space.com/s/ePmFyzNYj6bQbci). The set of SMARTS used for separating
the abovementioned sub-sets is available free of charge at https://cloud.chem-space.com/s/3DbC7KZeKGK4ZaW.
Received: 14 January 2023; Revised: 23 February 2023; Accepted: 5 March 2023
Copyright© 2023, O. V. Oksiuta, A. E. Pashenko, R. V. Smalii, D. M. Volochnyuk, S. V. Ryabukhin. This is an open access article under
the CC BY license (http://creativecommons.org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
DNA-Encoded Libraries Technology (DELT)
was first proposed as an idea by Brenner and Lerner
back in 1992 [1]. Since then it has become an ac-
tively developing tool for Drug Discovery, which
allows to generate the multi-billion screening mo-
lecules collection in a single vial [2] and identify
the hit molecules by decoding their unique DNA
tags. The synthesis of DNA-encoded chemical lib-
raries (DECLs) [3] is based on the split-and-pool
strategy [4, 5], which is a common combinatorial
chemistry approach topped with DNA fragments
as chipping tags. The most general sequence for
a DNA-encoded library synthesis is schematically
presented in Figure 1. Building-blocks and the
corresponding DNA tags are repeatedly connec-
ted to DNA primers from the opposing end (Figu-
re 1).
The most common approach to screening the
DNA-encoded libraries [6, 7] demands placing the
protein target of interest (POI) on the solid sup-
port bed and exposing it to the action of the set
of DNA-tagged molecules from the library (Figu-
re 2). The binders remain connected to the pro-
tein, and the non-binding molecules are washed
away (Figure 2). Then the binders (potential hits)
are eluted, their chemical structures are disclo-
sed using PCR sequencing of the coding DNA-
tags, and the data obtained is analyzed. At the
current stage of the DELT development, it is gra-
dually beginning to expand into more complex
biological assays, for instance cell-based assays
[8 – 11], which is a positive sign indicating the fle-
xibility and translation potential of DELT-based
platforms.
It is notable that the size of libraries created
using the DEL technology nowadays exceeds the
size of the conventional high-throughput screen-
ing (HTS) combinatorial libraries by several or-
ders of magnitude. The HTS libraries almost ne-
ver exceed one million individual compounds, while
3- and 4-cycle DNA-encoded libraries with the
input size of 1000 molecules on each cycle ge-
nerate a billion and a trillion molecules, respec-
tively.
The typical sequence for the four-cycle assem-
blies is given in Figure 3. It is worth mentioning
that there are also several approaches to DNA-
tagging, likewise double-strand [4, 12] and single-
strand [13] technologies. However, this technical
aspect is non-important for the current discus-
sion. Although traditionally viewed as the major
advantage, the gigantic size of the DELs also in-
troduces several risks and drawbacks. First of all,
chemical diversity of such libraries relies heavily
on the pool of reactions available for the DNA-
friendly environment [7, 14], as well as on the
sufficient number of suitable and available bi- and
tri-functional core building blocks (BBs) with or-
thogonal functional groups (FGs), and diverse mono-
functional molecules (capping agents) [15 – 19].
Another important factor influencing the success
of DEL-derived screening campaigns is the de-
velopment of the readout methods [4, 20, 21] and
statistical analysis of the hits [21 – 23].
ISSN 2308-8303 (Print) / 2518-1548 (Online) 5
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1)
DNA primer
first generation
second generation
Figure 1. Schematic representation of the split-and-pool process for the DNA-encoded library synthesis
Step 2. Screening of the DEL
for affinity to Protein-of-Interest (PoI)
on the solid support
Step 1. Taking previously
synthesi ed DEL for affinityz
selection
solid support
Step 3. Washing inactive
molecules out
Elution from PoI
Step 4. Identifying active
molecules
solid support
PCR amplification
Sequencing
Data analysis
Figure 2. Workflow for identifying an active molecule from DEL
Linear
Branched
Cyclic
Mono-functional
Bi-functional
Tri-functional
Conserved scaffold
Figure 3. Typical DEL sequence for a 4-step cycle with examples of mono-, bi-, tri-functional BBs
ISSN 2308-8303 (Print) / 2518-1548 (Online) 6
Журнал органічної та фармацевтичної хімії 2023, 21 (1)
As it is mentioned above, the main limitation
for DELT is the demand to use only such chemi-
cal transformations, which leave DNA fragments
intact. At the early stages of development, DELT
was used as a platform for amide couplings only
[24]; however, the overall advances in organic
synthesis techniques enabled the application of
a broad spectrum of chemical transformations
in DNA-tolerant conditions, including classical
C-C and C-N cross-couplings [25], metathesis
[26, 27], click reactions [17, 28 – 33], photoredox
reactions [34], and many others. Now that the
vast majority of common transformations used in
the cross-couplings has been successfully trans-
lated into on-DNA chemistry, and DELT is ap-
proaching the moment when the search for new
chemotypes again becomes a limiting factor.
In this connection, the cheminformatic algorithms,
such as eDESIGNER [35], which helps to design
libraries accounting both diversity and reaction
applicability factors, have been developed and re-
ported recently. Eventually, in the “maturation”
[36] process DELT replicates the evolutionary
route of traditional HTS-derived combinatorial
chemistry [37, 38] and is on a track from amide
coupling to more complex cross-coupling reac-
tions [39] and, finally, to the on-DNA heterocy-
cles formation. One can find a comprehensive re-
view on DNA-tolerant couplings described in mul-
tiple review articles [3, 14, 39, 40], however, the
works focused on the on-DNA heterocycles for-
mation started to show up in the periodical press
on a regular basis only recently. In this paper,
we aim to give an overview on the diversity of
DELT-suitable BBs for “traditional” cross-coupling
reactions based on the catalogue of stock mole-
cules provided by Enamine Ltd., and virtual set
provided by Chemspace Ltd., and evaluate the
potential contribution of the chemotypes emerg-
ing from the most recent discoveries in the field
of on-DNA heterocyclizations.
■ Results and discussion
For the decomposition of the pool of stock
(Enamine) building blocks we used the SMARTS set
(see the experimental part for details) specially
designed to account orthogonality of FGs in the
multifunctional compounds, the absence of unde-
sired functions (alkylators, moisture-sensitive
groups, etc.), and find compatible mono-functional
molecules or “capping agents” [19]. We distri-
buted the molecules obtained according to the
combination of functional and protective groups.
In case of stock polyfunctional cores, 11 classes of
bi-functional and 8 classes of tri-functional mo-
lecules were identified. We decided not to inclu-
de capping agents to our analysis. This is the most
widespread group having a decent overlap with
“traditional” monofunctional BBs commonly used
for combinatorial chemistry, and it hardly con-
tributes much to the chemical diversity, in con-
trast with rather scarce suitable multifunctional
core molecules. In case of stock BBs (Enamine),
26816 bi- and 1438 tri-functional “core” compounds
were obtained (Figures 4 and 5, respectively).
We performed the same type of extraction
using SMARTS and further analysis in Chem-
space (virtual) database. Additionally, the Synt-
On software package was used for this analysis
[41, 42]. Using Synt-On, 43 848 442 molecules in
33 sub-classes of, bi- and 3 119 488 molecules in
25 sub-classes of tri-functional BBs were iden-
tified. Low-reactive BBs and those with non-
orthogonal functional groups were removed.
The molecules obtained were combined into broa-
der classes as we did previously for stock com-
pounds. This approach allows to evaluate which
FGs and, consequently, which reactions contri-
bute the most to the DEL-derived chemical space.
Despite the insignificant shuffle in the “lower
bracket” of the histogram for bi-functional mole-
cules (Figure 6), the proportion between the most
widespread chemotypes in virtual space remains
close to the stock case (Figure 4). However, in
case of tri-functional cores, the fraction of acids,
which fulfill the selection criteria on the virtual
side (Figure 7), is significantly smaller than in
the stock (Figure 5). In all the remaining class-
es, the general trend for virtual structures cor-
relates with the stock. This observation led to
the conclusion that despite many reactions were
optimized for DNA-friendly conditions, the che-
mical diversity of DELs remains to the most
part to be limited to either amide- or ArX-amine
cross-couplings.
Introducing heterocycle formation reactions
is a beneficial way to expand the chemical space
of combinatorial chemistry-derived molecules,
which have proven itself in the HTS develop-
ment [43, 44]. It is also true that with the deve-
lopment of organic synthesis many heterocyclic
cores became readily available as scaffolds for
classical combinatorial chemistry, as well as
DEL-chemistry. Considering the growing num-
ber of publications focused on the on-DNA cycle
formation we assumed that DELT is about to cross
the same frontier as traditional combinatorial
ISSN 2308-8303 (Print) / 2518-1548 (Online) 7
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1)
chemistry did at the time when heterocycliza-
tions became noticeable part of the combinato-
rial reaction toolkit. In order to have a closer look
at this tendency, we studied the literature sour-
ces over the period from 2016 to 2020. We ob-
served the growing number of such publications
over time: a single one in 2015, and 14 in 2020.
We also identified 26 distinct types of the on-DNA
heterocycle formation reactions. They are sum-
marized in Table 1.
With this in mind, we wanted to study in more
detail if scaffolds from on-DNA heterocycliza-
tions occur as scaffolds in cross-coupling based
DEL builds. In other words, we wanted to look at
the population of heterocyclization-derived scaf-
folds in the bi- and tri-functional core BBs sub-
sets, and evaluate the potential contribution of he-
terocyclizations to the DELT-relevant chemical
space diversity. We used Synt-On to identify
scaffolds in both stock and virtual bi- and tri-
functional BBs sets, as well as in heterocycliza-
tion reactions products in Table 1. The latter pro-
vided 30 separate heterocyclic scaffolds. The scaf-
fold-inclusion analysis for the scaffolds from Ta-
ble 1 relative to bifunctional cores subclasses
(Table 2) and trifunctional core subclasses (Ta-
ble 3) was performed. The structure of Tables 2
and 3 is as follows: entry (subclass) number in
the first column; subclass abbreviation and an
overall number of compounds in the subclass;
“scaffolds in ref” shows how many times scaf-
folds from Table 1 are included “as is” or as sub-
structures to the BBs subclass scaffolds; in the
“molecules in ref” the number of molecules with
“sub-class” scaffolds, which contain the exact
structure of scaffolds from the heterocyclic set,
13472
9673
8418
8363
6109
2141
1041
704
573
427
260
0 2000 4000 6000 8000 10000 12000 14000 16000
Amine_FG
NHPG_FG
ArX_FG
Acid_FG
Ester_FG
Aldehyde_FG
Nitro_FG
Alkyne_FG
Boronate_FG
SO2X_FG
Azide_FG
Figure 4. Enamine stock bifunctional DEL-viable BBs, 26816 molecules in 11 classes
996
821
651
506
210
184
40
22
0 200 400 600 800 1000 1200
ArX_(FG)2
Acid_(FG)2
NHPG_(FG)2
Amine_(FG)2
Ester_(FG)2
Nitro_(FG)2
Aldehyde_(FG)2
Alkyne_(FG)2
Figure 5. Enamine stock trifunctional DEL-viable BBs, 1438 molecules in 8 classes
ISSN 2308-8303 (Print) / 2518-1548 (Online) 8
Журнал органічної та фармацевтичної хімії 2023, 21 (1)
or contain those as substructures, is given; the
“unique scaffolds” column contains data on how
many scaffolds are represented in the subclass;
the ”unique molecules” shows exactly how many
molecules contain “unique scaffolds”.
To summarize the data obtained, we com-
bined the results of our calculations into a sin-
gle table (Table 4). The latter shows the inclu-
sion of heterocyclization-derived scaffolds into
the overall pool of bi- and tri-functional BBs,
the stock (Enamine), as well as the virtual ones
(Chemspace). The results of this analysis are
not entirely expected: despite the fact that over
the half of the core BBs chemotypes used in the
heterocyclizations described in Table 1 remain
in DEL-chemistry for a long time (functional al-
dehydes, amines, etc.), their use in the reaction
types outside “traditional” cross-couplings im-
mediately provide more than 30 % of the scaffold
diversity in the entire DELT chemical extra-
space.
For better visualizing the outline from Table 4,
we constructed diagrams showing the contribu-
tion of the heterocyclic scaffolds to bifunctional
BBs space, both stock (Figure 8A) and virtual
(Figure 8B). We did the same for stock and vir-
tual trifunctional blocks (Figure 9A and 9B, re-
spectively).
35366119
22184906
14301221
5627307
2829764
250154
237588
3029451
1187202
2929
28750
0 5000000 10000000 15000000 20000000 25000000 30000000 35000000 40000000
Amine_FG
NHPG_FG
ArX_FG
Acid_FG
Ester_FG
Aldehyde_FG
Nitro_FG
Alkyne_FG
Boronate_FG
SO2X_FG
Azide_FG
Figure 6. Chemspace “tangible” virtual bifunctional DEL-viable BBs, 43 848 442 molecules in 11 classes
2505411
298722
1689153
2393330
167795
317919
784
27172
0 500000 1000000 1500000 2000000 2500000 3000000
ArX_(FG)2
Acid_(FG)2
NHPG_(FG)2
Amine_(FG)2
Ester_(FG)2
Nitro_(FG)2
Aldehyde_(FG)2
Alkyne_(FG)2
Figure 7. Chemspace “tangible” virtual trifunctional DEL-viable BBs, 3 119 488 molecules in 8 classes
ISSN 2308-8303 (Print) / 2518-1548 (Online) 9
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1)
Table 1. Heterocyclization reactions on DNA from the first case study to 2020
# Reaction Scaffold/Code
1 2 3
Reaction type: 5-membered Aromatic Rings formation
1. [31]
NH
O
Cu(II) cat., borate buffer
NH
O
N N
N
Ar
[B] = B(OH)2 or Bpin
TMS N3 Ar[B]
N
H
N
N
Scaf_01
2. [45]
NH
O
O
O R1 N
R2 NH2
TMS N3
NH
O
O
HN
R2
N N
N
N
R1
C
N
H
N N
N
Scaf_02
3. [45]
NH
O O
O
NH
O O
N
N
OC N N PPh3
NH
N
R1
R1 CO2H O
N N
Scaf_03
4. [46]
NH
C N
NH2OH
R
O
NH
O
N O
N R
CO2H O
N
N
Scaf_04
5. [47]
N
H N
H
NH2
S
R1
O
R2
Br
N
S
R1
R2 S
N
Scaf_05
Reaction type: 6-membered Aromatic Rings formation
6. [32]
N
H
O
N
N N
N
Me
OH
Cu(II) cat., bipyridine/TEMPO
DMSO/H2O
N
H
O
N
N
Me
OH
N
N
Scaf_06
7. [32]
N
H
O
N
N N
N
Me
proline, DMSO/H2O
N
H
O
N
N
Me
BocN O
NBoc
NHN
N
Scaf_07
8. [32]
N
H
O
N
N N
N
Me
DMSO/H2O
N
H
O
N
N
Me
R
R
N
N
Scaf_08
Reaction type: Fused Aromatic Rings formation
9. [48]
NH
O O
O
HN
O O
C N
Me
Me
Me
N
NH2
N
N
HN
Me
MeMe
N
N
Scaf_09
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1 2 3
10. [49] N
H
O
F
NO2
N
H
O
N
N
R2
R1 NH2
2. Reduction
1.
3. R2
O
R1
N
H
N
Scaf_10
Reaction type: Carbocyclic, 5 and 6-membered Non-Aromatic Rings formation
11. [50]
O
R
Ar
[Ir]
blue LED array
O
R
Ar
+
Scaf_11
12. [51]
N
O
NH2
OR
R1 R2
O
N
O
NH
R
R2
O
R1
1.
2.
NH
O
O
NH
N
H
Scaf_12
13. [27] N
H
N
O
N
H
O
N
[Ru]
N
H
Scaf_13
14. [49]
NH2
Br
O
MeO
R1
R2
N
O
R1
R2
+
O
N
H
Scaf_14
15. [49]
N
H
O
NH2
R2
OH
O
NH2
R1
N
H
O
N
NH
R2
R1
O
O
1.
2.
O
N
H
HN
Scaf_15
16. [52]
NH
O Zr(DS)4, ACN/H2OO
NH2
O2N
O Cl
O
NH
O
O
N O
Ph
1.
2.
O
N
H
O
Scaf_16
17. [52]
NH
O
O
Cl
O
Cl NH
O
O
N
Ph
Zr(DS)4, ACN/H2O
NH2
1.
2.
O NH
Scaf_17
18. [27] N
H
N
O
N
H
O
N
[Ru]
O
1-3
O
1-3
O
H
N
Scaf_18
O
H
N
Scaf_19
ONH
Scaf_20
Continuation of Table 1
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Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1)
Continuation of Table 1
1 2 3
Reaction type: Polycyclic Non-Aromatic Rings formation
19. [53]
N
H
O
S
N
O
O
R1R2
Pyrrolidine/BzOH
DMSO/H O2
NH
O
S
N O
OH
R1
R2
O
S
N
Scaf_21
20. [54] N
Ph
X
Me O
HN NH
O O
O
DIPEA
dioxane/H2O
N
Ph
X
HN
NH
O
O
O
X = CH Nor
ON
H
O
H
N O
NH
Scaf_22
ON
H
O
H
NN O
NH
Scaf_23
21. [55] N
Me
O
NH2
NH
N
Me
O
HN
H
N
R
OR
HN
N
H
Scaf_24
22. [56]
N
H
O
O
H
O
H2N
N
Boc
N
H
O
O
H
N
N
Boc
cat.
H2O
+
N
H
HN
Scaf_25
23. [51] O
O
O
O
O
O
N
OHO
O
R
H 1.
2.
R NH2
OO
NH
N
H
O
NH
Scaf_26
24. [57] N
H
O
O
Me
O
N
H
O
O
ON
Me
H
HMeNHOH
NaOAc aq buffer
OHN
O
Scaf_27
25. [58] N
H
O
O
H
O
N
H
H
N
R2R1
OH
3-4
[Au/AgSbF6]
O
N N
O
R1
R2
*
*
N
H
O
1-2+ aq. NH3/MeNH2
O NH
N
H
Scaf_28
O
N
H
NH
Scaf_29
26. [49] N
H
O
H
N
O NH2
R O
N
H
O
N NH
O
R
O
HN
N
H
Scaf_30
Notes:
1. – DNA fragment (double-stranded), ds-DNA
2. – DNA fragment (single-stranded), ss-DNA
3. – ss-DNA fragment on a solid support
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Table 2. The impact of heterocyclization-derived scaffolds to the bifunctional BBs chemical space
# Sub-class Scaffolds in ref Molecules in ref Unique scaffolds Unique molecules
1 Acid_Aldehyde 6 12 55 331
2 Acid_Alkyne 6 10 25 141
3 Acid_ArX 79 234 311 2440
4 Acid_Azide 13 24 21 71
5 Acid_Ester 23 71 95 521
6 Acid_Nboc 257 806 349 1919
7 Acid_Ncbz 10 28 23 84
8 Acid_NCS 0 0 2 7
9 Acid_Nfmoc 179 437 247 1509
10 Acid_Nitro 29 46 119 781
11 Aldehyde_ArX 20 54 92 820
12 Aldehyde_Azide 0 0 6 8
13 Aldehyde_Ester 11 37 68 368
14 Aldehyde_Nboc 53 115 86 262
15 Aldehyde_Nitro 7 11 46 222
16 Aldehyde_SO2X 0 0 4 12
17 Amino_Alkyne 23 63 59 430
18 Amino_ArX 177 422 577 3352
19 Amino_Azide 7 16 21 54
20 Amino_Ester 267 878 523 4047
21 ArX_AlkyneCH 2 4 18 108
22 ArX_ArX 57 168 232 1227
23 Azide_ArX 4 8 11 80
24 Azide_SO2X 0 0 3 17
25 Diamines_Nbn 67 131 75 205
26 Diamines_Nboc 302 807 469 1761
27 Diamines_Ncbz 11 18 19 46
28 Diamines_Nfmoc 3 7 9 11
29 Ester_Isocyanates 1 2 6 31
30 Ester_SO2X 9 29 43 372
31 Functional tetrazine 0 0 2 8
32 Functional_Boronates 21 40 90 562
33 Functional_BF3K 8 12 18 51
Table 3. The impact of heterocyclization-derived scaffolds to the trifunctional BBs chemical space
# Sub-class Scaffolds in ref Molecules in ref Unique scaffolds Unique molecules
1 2 3 4 5 6
1 1,3,5-Trisfunctionalised_benzenes 12 15 20 257
2 Acid_Aldehyde_AlkyneCH 0 0 1 1
3 Acid_Aldehyde_ArX 1 3 6 23
4 Acid_Aldehyde_Nitro 0 0 1 4
5 Acid_ArX_Ester 0 0 5 16
6 Acid_ArX_Nitro 0 0 9 71
7 Acid_Ester_Nitro 0 0 2 5
8 Amino_ArX_ArX 3 10 35 172
9 Amino_ArX_Nitro 0 0 13 102
10 ArX_ArX_ArX 3 4 27 93
11 ArX_ArX_Carboxy 9 27 27 201
12 Azide_ArX_Carboxy 0 0 0 0
13 NbocAA_AlkyneCH 1 2 4 16
14 NbocAA_ArX 4 6 18 69
15 NbocAA_Ester 4 10 4 30
16 NbocAA_Nitro 0 0 1 4
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1 2 3 4 5 6
17 NbocArX_Amino 10 11 29 40
18 NbocEsterAA_Aldehyde 3 3 7 10
19 NbocEsterAA_Amino 23 41 24 57
20 NbocNCbzAA 2 2 4 8
21 NbocNfmocAA 21 34 23 75
22 NfmocAA_alkyneCH 1 1 3 7
23 NfmocAA_ArX 17 20 15 54
24 NfmocAA_Ester 1 4 5 27
25 NfmocAA_Nitro 0 0 1 3
Continuation of Table 3
Table 4. The overall quantity of bi- and tri-functional molecules containing the generated scaffolds (stock and virtual)
# Scaffold (SMILES) Scaffold
Structure/Code
Bifunctional BBs Trifunctional BBs
Stock Virtual Stock Virtual
1 2 3 4 5 6 7
1 C1CCNC1 N
H
Scaf_12
2078 7871461 109 485045
2 C1CCC1
Scaf_11
1104 5941890 27 312303
3 S1C=CN=C1 S
N
Scaf_05
648 1533087 15 75218
4 C1COCCN1 O NH
Scaf_17
305 939622 3 51623
5 N1C=CN=N1 N
H
N
N
Scaf_01
175 660222 2 53908
6 C1=CC=NN=C1
N
N
Scaf_08
232 573015 33 52826
7 N1C=NC2=CC=CC=C12 N
H
N
Scaf_10
69 175965 0 3524
8 O1C=NC=N1 O
N
N
Scaf_04
39 156634 0 5888
9 N1C=NN=N1 N
H
N N
N
Scaf_02
29 103910 3 5056
10 C1NCC=C1 N
H
Scaf_13
21 57571 0 4304
11 C1=CN2C=CC=CC2=N1 N
N
Scaf_09
97 50346 5 1530
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1 2 3 4 5 6 7
12 O=C1NCCO1
O
N
H
O
Scaf_16
5 15795 0 756
13 O=C1CNCN1
O
N
H
HN
Scaf_15
5 4651 0 133
14 C1CC2=C(CN1)C=NN
=C2 NHN
N
Scaf_07
0 2694 0 16
15 O=C1NCCC2=CC=CC
=C12
O
NH
Scaf_26
2 274 0 5
16 O=C1NCC=C1
O
N
H
Scaf_14
2 253 0 11
17 C1CC2=C(CN1)NC1=C
C=CC=C21
HN
N
H
Scaf_24
10 220 0 2
18 O=C1CC=CCN1
O
H
N
Scaf_18
0 96 0 12
19 O=C1NCNC2=CC=CC
=C12
O
HN
N
H
Scaf_30
0 11 0 0
20 C1CC2(CCCCO2)NN1
O
N
H
NH
Scaf_29
0 0 0 0
21 C1CC2CNC3=CC=CC
=C3C2N1 N
H
HN
Scaf_25
0 0 0 0
22 C1ONC2C1COC1=CC
=CC=C21
OHN
O
Scaf_27
0 0 0 0
23 C1COC2(C1)CCNN2
O NH
N
H
Scaf_28
0 0 0 0
24 C1COC2=C(C1)SC=N2
O
S
N
Scaf_21
0 0 0 0
Continuation of Table 4
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Continuation of Table 4
1 2 3 4 5 6 7
25 C1CCCC2=C(CC1)C
=NN=C2 N
N
Scaf_06
0 0 0 0
26 O1C=NN=C1 O
N N
Scaf_03
0 0 0 0
27 O=C1CCC=CCN1
O
H
N
Scaf_19
0 0 0 0
28 O=C1CCCC=CCN1
ONH
Scaf_20
0 0 0 0
29 O=C1NC(=O)C2(CNC3=CC
=CC=C3C2)C(=O)N1
ON
H
O
H
N O
NH
Scaf_22
0 0 0 0
30 O=C1NC(=O)C2(CNC3=NC
=CC=C3C2)C(=O)N1
ON
H
O
H
NN O
NH
Scaf_23
0 0 0 0
2078
1104
648
305
232
175
97
69
Bifunctional BBs
-(in stock, range 1)
Scaf_12 Scaf_11 Scaf_05 Scaf_17
Scaf_08 Scaf_01 Scaf_09 Scaf_10
39
29
21
10
5
5
2
2
9
Scaf_04 Scaf_02 Scaf_13 Scaf_24
Scaf_16 Scaf_15 Scaf_26 Scaf_14
A
7871461
5941890
1533087
939622
660222
573015
175965
1409202
Bifunctional BBs
(virtual, range 1)
Scaf_12 Scaf_11 Scaf_05 Scaf_17
Scaf_01 Scaf_08 Scaf_10
156634
103910
57571
50346
15795
4651
269423140
Bifunctional BBs
(virtual, range 2)
Scaf_04 Scaf_02 Scaf_13 Scaf_09
Scaf_16 Scaf_15 Scaf_07
274
253
220
96
11107
Bifunctional BBs
(virtual, range 3)
Scaf_26 Scaf_14 Scaf_24
Scaf_18 Scaf_30
Bifunctional BBs
- 2(in stock, range )
B
341
Figure 8. The visualized impact of the on-DNA heterocyclization reactions-derived scaffold to the existing chemical space of stock (A)
and tangible virtual (B) bifunctional DEL-viable BBs
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■ Conclusions
We have analyzed both stock and virtual che-
mical spaces of bi- and tri-functional DELT-viable
building blocks using Enamine Ltd. stock collec-
tion (ca. 30000 molecules) and Chemspace Ltd.
tangible set (over 43 million structures) as case
studies. Despite seeming variability within both
groups (bi- and tri-functional BBs), the compounds
with functions suitable for classic cross-coupling
reactions, such as amide couplings or ArX – NHR2
couplings, namely acids, amines, protected amines
and aryl halides, vastly outnumber other func-
tional classes. The latter significantly limits both
current and nearest-time potential chemical di-
versity of the DNA-encoded libraries composed
on the basis of these types of BBs, especially on
the background of the huge size of such libra-
ries: literally what we get is massive numbers of
chemically homogeneous molecules, and it extre-
mely complicates readout at the stages of the bio-
logical testing. Considering the fact that in case
of the cross-coupling approach to the DEL syn-
thesis, the overwhelming majority of potentially
useful transformations were already adapted for
DNA-friendly conditions, one promising way to
approach better diversity of DEL chemical spa-
ce is to facilitate the synthesis of less common
classes of bi- and tri-functional cores like those
with sulfonyl halide, boronate, nitro- or aldehy-
de FGs. However, recent advances in on-DNA
heterocyclizations introduced some new chemo-
types to the field. Surprisingly, adding 30 scaf-
folds derived from 26 types of heterocyclizations,
even with many of these scaffolds already being
a part of the multifunctional cores space, has al-
lowed to expand the general scaffold diversity of
the chemical space observed by more than 30 %.
This finding clearly indicates that adapting the
existing and/or finding new heterocyclizations
suitable for DNA-friendly conditions, which first
and foremost could feed on the existing pool of
BBs, is another very potent way to expand the
scaffold diversity in DELs.
■ Acknowledgments
The authors express their gratitude to Ena-
mine Ltd. and Chemspace Ltd. for granting access
to their data sets, and personally to Prof. And-
rey A. Tolmachev for encouragement and compre-
hensive support in preparing the manuscript.
109
33 27
15
5
3
3 2
8
Trifunctional BBs
-(in stock)-
Scaf_12 Scaf_08 Scaf_11 Scaf_05
Scaf_09 Scaf_17 Scaf_02 Scaf_01
A
B
485045
312303
75218
53908
52826
51623
104449
Trifunctional BBs
(virtual, range 1)
Scaf_12 Scaf_11 Scaf_05
Scaf_01 Scaf_08 Scaf_17
5888
5056
4304
3524
1530
756
133
2419
Scaf_04 Scaf_02 Scaf_13 Scaf_10
Scaf_09 Scaf_16 Scaf_15
Trifunctional BBs
2(virtual, range )
16
12
11
5
2
7
Scaf_07 Scaf_18 Scaf_14
Scaf_26 Scaf_24
Trifunctional BBs
3(virtual, range )
Figure 9. The visualized impact of the on-DNA heterocyclization reactions-derived scaffold to the existing chemical space of stock (A)
and tangible virtual (B) trifunctional DEL-viable BBs
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Journal of Organic and Pharmaceutical Chemistry 2023, 21 (1)
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Information about the authors:
Oleksandr V. Oksiuta, Ph.D. Student of the Biologically Active Compounds Department, Institute of Organic Chemistry of the National
Academy of Sciences of Ukraine; Data Scientist at Chemspace Ltd.; https://orcid.org/0000-0003-3049-0373.
Alexander E. Pashenko, Ph.D. in Chemistry, Junior Researcher of the Department of Physicochemical Investigations, Institute of Organic
Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0001-6157-0785.
Radomyr V. Smalii, Ph.D. in Chemistry, Project Manager at Enamine Ltd.; https://orcid.org/0000-0003-0379-1138.
Dmitriy M. Volochnyuk (corresponding author), Dr.Sci. in Chemistry, Professor of the Supramolecular Chemistry Department,
Institute of High Technologies, Taras Shevchenko National University of Kyiv; Head of the Biologically Active Compounds Department,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Senior Scientific Advisor, Enamine Ltd.;
https://orcid.org/0000-0001-6519-1467; e-mail for correspondence: d.volochnyuk@gmail.com.
Sergey V. Ryabukhin (corresponding author), Dr.Sci. in Chemistry, Professor, Head of the Supramolecular Chemistry Department,
Institute of High Technologies, Taras Shevchenko National University of Kyiv; Senior Scientific Advisor, Enamine Ltd.; Senior Researcher
of the Department of Physicochemical Investigations, Institute of Organic Chemistry of the National Academy of Sciences of Ukraine;
https://orcid.org/0000-0003-4281-8268; e-mail for correspondence: s.v.ryabukhin@gmail.com.
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| id | oai:ojs.journals.uran.ua:article-275133 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-24T01:00:33Z |
| publishDate | 2023 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/9e/cce20058367cf80698d066ab003fe39e.pdf |
| spelling | oai:ojs.journals.uran.ua:article-2751332026-08-23T20:00:17Z Heterocyclization vs Coupling Reactions: A DNA-Encoded Libraries Case Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек Oksiuta, Oleksandr V. Pashenko, Alexander E. Smalii, Radomyr V. Volochnyuk, Dmitry M. Ryabukhin, Serhii V. DNA-encoded libraries technology orthogonal functional groups coupling reactions polyfunctional building blocks heterocyclizations chemoinformatics scaffold diversity технологія ДНК-кодованих бібліотек ортогональні функціональні групи реакції каплінгу поліфункціональні білдинг-блоки гетероциклізації хемоінформатика разноманітність молекулярних каркасів Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity. Мета. Технології ДНК-кодованих бібліотек (DELT) поступово стають важливою частиною стандартного набору інструментів для пошуку нових лікарських субстанцій. Наразі DELT прагне знайти своє місце у просторі між класичними низькомолекулярними кандидатами у ліки з одного боку та високомолекулярними антитілами й пептидами з іншого. На своєму шляху до подолання «дитячих хвороб», характерних для кожної нової технології, DELT досягли того моменту, коли хімічна різноманітність ДНК-кодованих бібліотек (DEL) стає важливим фактором, на який варто звернути увагу. У цій статті ми прагнемо ближче розглянути хімічне різноманіття ДНК-кодованих бібліотек у їхньому поточному стані та знайти можливості для його покращення.Результати та їх обговорення. Ми визначили DEL-життєздатні будівельні блоки з наявної колекції Enamine Ltd., а також із віртуальної колекції Chemspace Ltd., використовуючи набір SMARTS, який враховує всі необхідні структурні обмеження. За допомогою таких сучасних інструментів хемоінформатики, як Synt-On, ми проаналізували різноманітність каркасів як уже синтезованих, так і віртуальних бі- та трифункціональних білдинг-блоків (BB), придатних для реакцій, у яких ДНК залишається інтактною. Ідентифікація молекулярних скафолдів, використовуваних у нещодавно опублікованих «on-DNA» реакціях гетероциклізації, та аналіз їх внесення до простору BB, який існує, засвідчили, що нові толерантні до ДНК гетероциклізації є надзвичайно корисними для розширення хімічної різноманітності в технологіях DEL.Висновки. Виконаний аналіз дозволив нам визначити, яким функціональним групам варто віддати пріоритет як найбільш впливовим у процесі дизайну нових BB. Також стало зрозуміло, що розвиток нових толерантних до ДНК реакцій, включаючи гетероциклізації, має значний потенціал для подальшого розширення молекулярного різноманіття DEL. National University of Pharmacy 2023-06-03 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/275133 10.24959/ophcj.23.275133 Journal of Organic and Pharmaceutical Chemistry; Vol. 21 No. 1 (2023); 3-19 Журнал органической и фармацевтической химии; Том 21 № 1 (2023); 3-19 Журнал органічної та фармацевтичної хімії; Том 21 № 1 (2023); 3-19 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/275133/273037 Copyright (c) 2023 Oleksandr V. Oksiuta, Alexander E. Pashenko, Radomyr V. Smalii, Dmitry M. Volochnyuk, Serhii V. Ryabukhin http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | технологія ДНК-кодованих бібліотек ортогональні функціональні групи реакції каплінгу поліфункціональні білдинг-блоки гетероциклізації хемоінформатика разноманітність молекулярних каркасів Oksiuta, Oleksandr V. Pashenko, Alexander E. Smalii, Radomyr V. Volochnyuk, Dmitry M. Ryabukhin, Serhii V. Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title | Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title_alt | Heterocyclization vs Coupling Reactions: A DNA-Encoded Libraries Case |
| title_full | Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title_fullStr | Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title_full_unstemmed | Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title_short | Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек |
| title_sort | гетероциклізація або реакції каплінгу: випадок днк-кодованих бібліотек |
| topic | технологія ДНК-кодованих бібліотек ортогональні функціональні групи реакції каплінгу поліфункціональні білдинг-блоки гетероциклізації хемоінформатика разноманітність молекулярних каркасів |
| topic_facet | DNA-encoded libraries technology orthogonal functional groups coupling reactions polyfunctional building blocks heterocyclizations chemoinformatics scaffold diversity технологія ДНК-кодованих бібліотек ортогональні функціональні групи реакції каплінгу поліфункціональні білдинг-блоки гетероциклізації хемоінформатика разноманітність молекулярних каркасів |
| url | https://ophcj.nuph.edu.ua/article/view/275133 |
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