Rational design of protein kinase inhibitors
Modern methodological approaches to rational design of low molecular weight compounds with specific activity in relation to predetermined biomolecular targets are considered by example of development of high effective protein kinase inhibitors. The application of new computational methods that allow...
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| Cite this: | Rational design of protein kinase inhibitors / S.M. Yarmoluk, A.Yu. Nyporko, V.G. Bdzhola // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 339-347. — Бібліогр.: 44 назв. — англ. |
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nasplib_isofts_kiev_ua-123456789-1529952025-02-23T19:00:19Z Rational design of protein kinase inhibitors Раціональний дизайн інгібіторів протеїнкіназ Рациональный дизайн ингибиторов протеинкиназ Yarmoluk, S.M. Nyporko, A.Yu. Bdzhola, V.G. Reviews Modern methodological approaches to rational design of low molecular weight compounds with specific activity in relation to predetermined biomolecular targets are considered by example of development of high effective protein kinase inhibitors. The application of new computational methods that allow to significantly improve the quality of computational experiments (in, particular, accuracy of low molecular weight compounds activity prediction) without increase of computational and time costs are highlighted. The effectiveness of strategy of rational design is demonstrated by examples of several own investigations devoted to development of new inhibitors that are high effective and selective towards protein kinases CK2, FGFR1 and ASK1. Сучасні методологічні підходи до раціонального дизайну низькомолекулярних сполук, що характеризуються специфічною активністю щодо заданих біомолекулярних мішеней, розглянуто на прикладі розробки високоефективних інгібіторів протеїнкіназ. Висвітлено нові обчислювальні методи, застосування яких дає змогу суттєво покращити якість комп’ютерних експериментів (зокрема, точність передбачення активності низькомолекулярних сполук) без збільшення розрахункових потужностей та витрати часу. Ефективність стратегії раціонального дизайну підтверджено низкою власних досліджень з розробки нових інгібіторів протеїнкіназ СК2, FGFR1 і ASK1. Современные методологические подходы к рациональному дизайну низкомолекулярных соединений, характеризующихся специфической активностью по отношению к заданным биомолекулярным мишеням, рассмотрены на примере разработки высокоэффективных ингибиторов протеинкиназ. Освещены новые вычислительные методы, применение которых дает возможность значительно улучшить качество компьютерных экспериментнов (в частности, точность предсказания активности низкомолекулярных соединений) без увеличения расчетных мощностей и затрат времени. Эффективность стратегии рационального дизайна подтверждена рядом собственных исследований по созданию новых ингибиторов протеинкиназ СК2, FGFR1 и ASK1. 2013 Article Rational design of protein kinase inhibitors / S.M. Yarmoluk, A.Yu. Nyporko, V.G. Bdzhola // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 339-347. — Бібліогр.: 44 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000828 https://nasplib.isofts.kiev.ua/handle/123456789/152995 577.322, 577.152.271 en Вiopolymers and Cell application/pdf Інститут молекулярної біології і генетики НАН України |
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Modern methodological approaches to rational design of low molecular weight compounds with specific activity in relation to predetermined biomolecular targets are considered by example of development of high effective protein kinase inhibitors. The application of new computational methods that allow to significantly improve the quality of computational experiments (in, particular, accuracy of low molecular weight compounds activity prediction) without increase of computational and time costs are highlighted. The effectiveness of strategy of rational design is demonstrated by examples of several own investigations devoted to development of new inhibitors that are high effective and selective towards protein kinases CK2, FGFR1 and ASK1. |
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Article |
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Yarmoluk, S.M. Nyporko, A.Yu. Bdzhola, V.G. |
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Yarmoluk, S.M. Nyporko, A.Yu. Bdzhola, V.G. |
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Yarmoluk, S.M. |
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Rational design of protein kinase inhibitors |
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Rational design of protein kinase inhibitors |
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Rational design of protein kinase inhibitors |
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Rational design of protein kinase inhibitors |
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Rational design of protein kinase inhibitors |
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rational design of protein kinase inhibitors |
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Інститут молекулярної біології і генетики НАН України |
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Rational design of protein kinase inhibitors / S.M. Yarmoluk, A.Yu. Nyporko, V.G. Bdzhola // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 339-347. — Бібліогр.: 44 назв. — англ. |
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Вiopolymers and Cell |
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UDC 577.322, 577.152.271
Rational design of protein kinase inhibitors
S. M. Yarmoluk, A. Yu. Nyporko, V. G. Bdzhola
Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnogo Str., Kyiv, Ukraine 03680
sergiy@yarmoluk.org.ua
Modern methodological approaches to rational design of low molecular weight compounds with specific activi-
ty in relation to predetermined biomolecular targets are considered by example of development of high effective
protein kinase inhibitors. The application of new computational methods that allow to significantly improve the
quality of computational experiments (in, particular, accuracy of low molecular weight compounds activity pre-
diction) without increase of computational and time costs are highlighted. The effectiveness of strategy of rational
design is demonstrated by examples of several own investigations devoted to development of new inhibitors that
are high effective and selective towards protein kinases CK2, FGFR1 and ASK1.
Keywords: rational desing, protein kinase inhibitors, low molecular weight compounds, protein kinases ÑÊ2,
FGFR1 and ASK1.
Introduction. Kinases are almost widest family of hu-
man enzymes – about 1.7 % of all proteins, encoded in
human genome, are protein kinases [1], which in
couple with their antagonists protein phosphatases re-
gulate numerous metabolic processes in eukaryotic cell
via control of protein phosphorylation level. The trans-
fer of the phosphate group to the amino acid residue of
the substrate protein is one of key stages in the start and
transmission of intracellular signaling, responsible for
cell cycle progress, cell differentiation, intercellular and
cell–substrate interactions, cell motility, immune respon-
se, channel and transporter activity, processes of transcrip-
tion, translation and main metabolism. The majority of
protein kinases contain at least one residue of hydroxy
amino acid, the phosphorylation of which causes confor-
mational changes and, as consequence, the transition of
protein kinase into active form [2– 4]. Constitutively ac-
tive kinases are an exception.
Total involvement of protein kinases into metabolic
processes has its downside – a lot of protein kinases are
key factors of genesis of various dangerous diseases.
Among kinase-dependent pathologies one should men-
tion diabetes, inflammatory processes of various etiolo-
gy, cardiovascular diseases, pathogenesis of several in-
fectious diseases as well as numerous of oncological di-
seases [5–6].
Taking into consideration the crucial role of protein
kinases in the regulation of proteome status, their study
should be conducted using a specific set of molecular
instruments of sophisticated control of the activity of in-
dividual protein kinases. These molecular instruments
may be protein kinase inhibitors characterized by a high
degree of selectivity. The availability of these inhibitors
would allow to «switch off» certain protein kinases and
observe metabolic consequences of such targeted effect,
which would expand the current views on both kinome
functions and metabolome in general. At the same time
these inhibitors could be used as a basis for the develop-
ment of high efficient drugs for treatment of oncological
and other human diseases.
It’s completely logical that the development of effec-
tive and selective protein kinases inhibitors and newest
drugs on their base is one of vital tasks of modern phar-
macology [7–9]. Bibliographic database of National Cen-
339
ISSN 0233–7657. Biopolymers and Cell. 2013. Vol. 29. N 4. P. 339–347 doi: 10.7124/bc.000828
� Institute of Molecular Biology and Genetics, NAS of Ukraine, 2013
340
ter for Biotechnological Information of USA PubMed
contains about 5000 references to works relating to
design of compounds capable to inhibit protein
kinases. However, one should mention that at the end of
last year the only sixteen or so compounds were
approved as drugs despite numerous researches in this
field [10].
Strategy of rational design of protein kinase in-
hibitors. A conventional strategy of rational design of
protein kinase inhibitors is based on the fine understan-
ding of structural mechanisms of specific binding of low
molecular weight organic compounds with these enzy-
mes. According to the mechanism of interaction, the
protein kinase inhibitors are divided into three groups
[9, 11]. The first and probably the widest group consists
of the compounds that are able to directly interact with
ATP binding site of protein kinases (type I inhibitors).
They contain classical donors and acceptors of hydro-
gen bond and form at least one such bond with a hinge
region of the site, which in norm is the place of adenine
binding. While interacting with type I inhibitors, kinases
are in activated (phosphorylated) state. Type I inhibi-
tors are various chemical analogues of nucleobases. It
is natural that type I inhibitors are generally characte-
rized by a low level of selectivity. However, several se-
lective representatives of these compounds are not only
are discovered but approved for clinical use, in particu-
lar, fasudil, gefitinib (iressa), erlotinib, sunitinib and
dasatinib.
Contrary to type I inhibitors, type II inhibitors inter-
act with the so called extended ATP binding site of in-
activated protein kinase. Besides the sites of binding
adenine, ribose and phosphate, which are very conser-
vative for all protein kinases, this site also contains an
additional hydrophobic pocket that opens due to confor-
mational changes during the transition of protein kina-
se from the active state into the inactive one. This po-
cket is less conservative for its amino acid content, and
type II inhibitors a priori demonstrate higher selectivi-
ty compared to type I inhibitors. Type II inhibitors are
approved for clinical use, include such compounds as
imatinib (well-known by its trade name, glivec), sorafe-
nib (nexavar), lapatinib, nilotinib [9, 10].
Type III inhibitors are completely allosteric; they
have individual sites of interaction and, contrary to two
previous types, do not compete with ATP [9, 10]. The-
se compounds demonstrate the highest degree of selec-
tivity, however, the number of known type III inhibi-
tors is few and none of them approved as a medicine.
The search or design of new inhibitors interacting with
allosteric sites could be promising due to their high se-
lectivity but the lack of information about allosteric
sites on the surface of many protein kinases extremely
limits the possibilities of the rational design of these
compounds.
Taking the above mentioned into consideration, it
is reasonable that the rational design of selective inhibi-
tors of kinases as rule is based on the development of
compounds able to specifically interact with ATP bin-
ding sites, i. e. type I and II inhibitors, introducing cor-
responding substituents interacting with «surrounding»
(allosteric) sites.
The strategy of the rational design is concerted com-
bination of computational approaches used for detailed
analysis of structural mechanisms of inhibitors inter-
action with molecules of protein kinases and their affini-
ty predicted with instrumental methods of estimation of
activity and selectivity of the developed compounds.
The procedure of the rational design consists of the fol-
lowing stages:
– target selection;
– analysis of individual specificities of the spatial
structure of ATP-binding and allosteric sites of target
protein kinases;
– high-throughput receptor-based virtual screening
of the database of low molecular weight organic com-
pounds and determination of classes of compounds with
the highest in silico affinity to target protein kinases;
– experimental verification of the inhibitor activity
and selectivity of the most promising compounds
accordantly to data of the previous stage on set of target
protein kinases in vitro;
– correlative analysis of structure activity relation-
ship (SAR) using the results of biochemical assays and
determination of hit compounds for subsequent che-
mical optimization;
– synthesis and chemical optimization of new inhi-
bitors based on SAR analysis, selectivity and computa-
tional modelling data.
New computational approaches. In silico methods
are good productive for search of low molecular weight
compounds with predetermined specific activity in rela-
YARMOLUK S. M., NYPORKO A. Yu., BDZHOLA V. G.
tion to specified biomolecular targets. They allow to ra-
tionally restrict range of compounds for the next wet
experiments and, thus, to reduce the time and cost for the
development of new biologically active compounds with
targeted effect and new drugs in particular. However,
when researchers apply them for the tasks of high-
throughput virtual screening (HTVS), they have to use
simplified estimating methods that downshift the affini-
ty and/or activity prediction.
Yakovenko et al. [12–14] developed and introdu-
ced a number of new computational methods allowing
to essentially improve the quality of computational
experiments without any increase in estimation capa-
city and time.
Due to large size of biomolecular systems the high-
ly efficient quantum methods of simulating intermo-
lecular interactions in HTVS are rarely used. The force
field method, based on Coulomb interaction, is used in-
stead since it provides simple calculation and requires
only the data on the electric charge distribution on atoms
of the analysed compounds. Based on the principle of
electronegativity relaxation of the Kirchhoff charge mo-
del, an original method is developed to determine the
distribution of the electric charge [13], which presents
the electric density distribution as a discrete set of point
charges localized on atoms. Similar approach previous-
ly described in [15] contains several disadvantages re-
sulting in method constant bias and the reduction of its
performance.
The authors not only improved the formalism of the
electronegativity relaxation method but also performed
its parameterization by quantum approaches at the HF/
6-311++G(d, p) level of theory. On average the devia-
tion in reproducing the experimental values of dipole
and quadruple moments of organic molecules using the
developed method does not exceed 0.3 D and 0.2 B, res-
pectively [13]. The developed method is universal and
differs from well-known empirical methods by its per-
formance and high accuracy of reproducing of the
charge distribution on the atoms of organic molecules.
The same authors designed a new force field (FF)
YFF1 for further estimation of intermolecular interac-
tions in HTVS [14] which combines the authors’ scheme
of atomic charges calculation [13] and basic parameteri-
zation of covalent and van der Waals interactions of the
force field MMFF94, specifically parameterized for the
reproduction of interactions in the «biopolymer–li-
gand» systems [16].
FF YFF1 enhances the accuracy of computation of
electrostatic interactions, declared in FF MMFF94, by at
least an order (average deviation of reproducing elect-
ric moments is 0.8–1.2 D) and is the best among other
FF to estimate the energy of intermolecular interactions
in the «protein–ligand» systems. A software complex,
ensuring automatic compilation of free organic structu-
re in FF YFF1, is designed [14].
The ligand solvatation energy should be taken into
account for the accurate estimation of ligand affinity to
the receptor. To use in the HTVS tasks, the same authors
modified the formalism of computation of solvatation
energies of ligands compared to GBSA model [17, 18]
by increasing the response rate of the algorithm via the
introduction of effective Born radius estimation [19].
The modified GBSA model was tested on a set of > 400
compounds of various classes with experimentally defi-
ned values of desolvatation energy. The obtained value
of linear correlation coefficient between predicted and
experimentally defined values is 0.84 which is current-
ly the highest for known empirical methods of GBSA
family [20].
Yakovenko et al. used the formalism of function of
the states distribution of molecular assembly by the de-
gree of freedom for the estimation of molecular affinity
with the consideration of entropy effects. A unique me-
thod was designed to assess the functions of distribu-
tion for both rotational and translational as well as for
internal degrees of freedom for molecular complexes.
As the accuracy criterion for the prognosis of intermole-
cular affinities was chosen the anticipation of experi-
mentally defined inhibition constants (Ki) for the enzy-
me inhibitors, since this parameter does not depend on
the conditions of its determination, on the substrate con-
centration in particular [20].
The developed models and algorithms were used in
the department of medicinal chemistry to create the la-
boratory program complex for HTVS of low molecu-
lar organic compounds. This is the first Ukrainian
program complex that is applied for drug search and
development.
The application of developed novel computational
approaches to the procedure of rational design provided
the successful development of new efficient inhibitors
341
RATIONAL DESIGN OF PROTEIN KINASE INHIBITORS
of several protein kinases, in particular CK2, FGFR1
and ASK1.
Inhibitors of protein kinase CK2. An extremely
attractive target for the search of inhibitors among the
representatives of serine-threonine protein kinases is a
highly conservative CK2 (casein kinase 2), presented in
all the eukaryotic organisms [21–24]. CK2 has over 400
physiological targets (factors of growth and transcrip-
tion, regulators of cellular cycle and apoptosis, compo-
nents of response to stress, etc.) [25–28], while its overex-
pression results in the development of a number of pa-
thologies, including oncological diseases [29–34], Alz-
heimer’s disease [35], glomerulonephritis [36], inflam-
matory processes [37], a number of viral infections [27],
diabetes-associated eye diseases [38]. Therefore, selec-
tive inhibitors of CK2 may be important key for study of
cell signaling pathways as well as successfully use in me-
dical practice.
High-throughput virtual screening of the database
of compounds of department of medicinal chemistry of
IMBG NASU, biochemical testing in vitro and subse-
quent chemical optimization allowed to develop new se-
lective inhibitors of CK2. Despite the numerous works in
the search of CK2 inhibitors, namely the scientific team
of the IMBG medicinal chemistry department has the
first officially registered patents for inhibitors of this
protein kinase – UA68984 and UA69165 [39]. The in-
hibitory activity of such classes of compounds as 3 car-
boxy-4-(1H)-quinolones [40, 41] and tetrahalogeno-
1,3-dioxo-2,3-dihydroisoindoles [42, 43] was demon-
strated for the first time.
These compounds interact with CK2 via a common
mechanism, forming hydrogen bonds with aminoacid re-
sidues Lys 68, Asp175, Glu81, Trp176 and forming
hydrophobic contacts with residues Phe113, Val66,
Val53, Ile174.
Among the derivatives of 3 carboxy-4-(1H)-quino-
lones, the highest inhibitory activity was registered for
compounds 3.7 (5,6,8-trichloro-4-oxo-1,4-dihydroqui-
noline-3-carboxylic acid) and 3.55 (7,8-dichloro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid), charac-
terized by nanomolar values of Ki (60 and 150 nM) and
IC50 (300 and 800 nM, respectively) [40, 41]. For com-
pound 3.7, high level of selectivity was also determi-
ned. On the testing panel consisting of 7 kinases only in
case of protein kinase DYRK1a the some inhibition
was revealed, but this is typical for other selective
inhibitors of CK2 kinase [44].
The tetrahalogeno-1,3-dioxo-2,3-dihydroisoindoles
also have a number of compounds capable to inhibit
CK2 in nanomolar concentrations. Among the repre-
sentatives of this class the most active one is TID46 2-
(4,5,6,7-iodo-1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)
propanoic acid with IC50 150 nM and the inhibition con-
stant value of 100 nM. The results of testing selectivity
of inhibitors affecting protein kinases DYRK1a, MSK1,
GSK3 and CDK5 demonstrated that in the concentra-
tion of 10 µM this compound causes insignificant inhi-
bition of these kinases [42, 43].
The ability to inhibit CK2 was also revealed for de-
rivatives of 4-aminoquinazoline and 4-amino-3-carb-
etoxyquinoline [45, 46]. It was previously demonstra-
ted that tyrphostin AG1478 (4-(3-chloroanilino)-6,7-
dimethoxyquinazoline) is able to inhibit CK2 activity
[47]. Among the representatives of these classes there
were no compound, capable to inhibit CK2 in nano-
molar concentrations, but the optimization of inhibi-
tors, for instance, via glycosylation in certain positions,
allowed decreasing IC50 from 7.7 to 3 µM for 4-amino-
quinazolines and from 9 to 2 µM for 4-amino-3-carb-
etoxyquinolines.
The several compounds with high CK2-inhibiting
activity were obtained via optimization of derivatives
of flavones on the basis of developed models of their
interaction with the kinase. For instance, 26 out of 28
synthesized de novo derivatives of 4'-hydroxyflavone
(92.8 %) were characterized by nanomolar activity va-
lues. The most efficient among them were compounds
FNH68 (6,8-dichloro-2-(4-hydroxy-3-methoxyphenyl)-
chromen-4-on) – IC50 = 10 nM, Ki = = 3.6 nM – and
FNH79 (6,8-dibromo-2-(4-hydroxy-3-methoxyphenyl)-
chromen-4-on) – IC50 = 4 nM, Ki = 1.8 nM, also charac-
terized by high levels of selectivity on the panel of tes-
ting protein kinases.
Among other types of flavone derivatives, the es-
sential CK2-inhibiting activity is shown for some re-
presentatives of 4'-carboxyflavonols [48]. The optimi-
zation of 3-hydroxy-2-phenyl-chromen-4-on by the in-
troduction of substituents into positions 6 and 8 allow-
ed to obtain the panel of 13 new derivatives. They all had
submicromolar (nanomolar) values of IC50. The most
active compounds are FLC21 4-(6,8-dichloro-3-hydro-
342
YARMOLUK S. M., NYPORKO A. Yu., BDZHOLA V. G.
xy-4-oxo-4H-chromen-2-yl)benzoic acid and FLC26
4-(6,8-dibromo-3-hydroxy-4-oxo-4H-chromen-2-yl)
benzoic acid (IC50 – 40 and 9 nM, Ki – 13 and 2.5 nM,
respectively). In addition, FLC26 demonstrated high
selectivity level regarding CK2 compared to other tes-
ted kinases (ASK1, Jnk 3, FGFR1, Met, Aurora A, Tie
2 and Rock 1) [48].
All active flavone inhibitors have a similar type of
binding. In all obtained «CK2–inhibitor» complexes the
hydrophobic contacts were formed between the ligand
and seven aminoacid residues (Leu45, Val53, Val66,
Ile 95, Phe113, Met163 and Ile174). The interaction of
the phenol ring in position 2 of heterocycle with Phe
113, Ile95 and Ile174 is especially important. The con-
tact with Phe113 is realized via stacking interaction,
which is of great importance for the fixation of the in-
hibitor in ATP-binding site. Other key interactions are
two intermolecular hydrogen bonds, involving the hin-
ge region (Val116) and pocket (Lys68) that is located
deep in the CK2 binding site. The formation of hydro-
gen bonds in the hinge region is typical for the majority
of protein kinase inhibitors, which was confirmed by
numerous data of X-ray structural analysis [9]. All this
testifies about complementarity of flavones to ATP-bin-
ding site of CK2 and their availability for chemical opti-
mization, which was demonstrated in the investiga-
tions [48].
The inhibitors of protein kinase CK2 were first
found among the derivatives of thieno[2,3-d]pyrimi-
dine [49]. Thienopyrimidines are known as inhibitors
of ErbB, PDGF, VEGFR-2, FLT3 and Tie2 kinases
[50–52], but there were no data on their CK2-inhibiting
activity. The highest activity was demonstrated by com-
pound TTP22 3-(5-p-tolyl-thieno[2,3-d]pyrimidine-4-
yl-sulfanyl)-propionic acid: its IC50 is 0.1 µM, while Ki
is 40 nM. This compound is also characterized by fine
selectivity on the panel of four serine/threonine (ASK1,
JNK3, Aurora A and Rock 1) and three tyrosine protein
kinases (FGFR1, Met and Tie2), except for the ability of
inhibiting the activity of kinase Aurora A (residual ac-
tivity 23 % at the concentration of 10 µM).
The key contacts promoting the binding of thieno
[2,3-d]pyrimidine inhibitors by CK2 molecule are van
der Waals interactions, occurring between the ligand
and a number of hydrophobic residues (Leu45, Val53,
Val66, Val116 and Ile174). In addition, the compounds
form three intermolecular hydrogen bonds in ATP-bin-
ding site of CK2. One bond is formed between nitrogen
atom in position 1 of thieno[2,3-d]pyrimidine hetero-
cycle and Val116 of the hinge region of CK2. Two other
bonds are formed by the substitute R4 (propionic acid)
in the hydrophobic region 1 of the active site. The first
bond occurs with side chain Lys68, and the second one –
with the main chain Asp175.
Inhibitors of protein kinase FGFR1. An attracti-
ve target for inhibitor design among the representatives
of tyrosine kinases is FGFR1 participating in the forma-
tion of mesenchymal tissue, the nervous system, lungs,
mammary glands during embryogenesis, and it is invol-
ved in reparative processes and tissue homeostasis,
inflammation, angiogenesis, differentiation of muscle
and fat cells [53]. The overexpression of FGFR1 was re-
gistered for several oncological diseases (glioblastoma,
breast cancer, prostate cancer, lymphoma, melanoma,
etc.) [54].
At present there are only a few known inhibitors of
FGFR1 [55], some of which are at the clinical trial sta-
ge, but these compounds are active towards the whole fa-
mily of FGFR protein kinases due to considerable struc-
tural similarity of the enzymes, especially in the kinase
domain (TKI-258 (Novartis), Brivanib (Bristol Myers
Squibb), E7080 (Eisai), AZD4547 (Astra Zeneca)).
The most selective class of FGFR1 inhibitors – pyrido-
pyrimidines – did not pass clinical trials because of their
high toxicity and is used for research only [55].
The ability to inhibit the activity of FGFR1 was de-
monstrated by us regarding flavones, oxyindoles and
quinasolines. These compounds demonstrate inhibito-
ry properties under condition of heterocycle interac-
tion with the hinge region (the formation of the hydro-
gen bond) and the presence of the phenol ring linked to
the main heterocycle by a flexible spacer and directed
towards the hydrophobic pocket 1 FGFR1. The affinity
of ligands to FGFR1 is considerably dependended on
the nature of substituents in the phenol ring [56–58].
As stated above, the derivatives of flavones are inhi-
bitors of several of protein kinases, in particular, cyc-
lin-dependent kinases [59] and CK2 [48, 60]. Their anti-
tumor and anti-angiogenic activity was revealed in mic-
romolar range of concentrations [61]. According to the
results of biological testing, 6 flavone compounds have
IC50 under 25 µM. The ligand with high FGFR1-inhi-
343
RATIONAL DESIGN OF PROTEIN KINASE INHIBITORS
bitory activity belongs to the structural subclass of fla-
vonols, and the highest effect is demonstrated by the
compounds with the substituents in position 3 of the chro-
men heterocycle, a hydroxyl group, in particular [56].
According to the developed model of interaction of
flavonols with FGFR1, phenol radical is oriented inside
the binding site. The formation of two hydrogen bonds
is possible between the carboxylic and hydroxyl groups
of chromen and hinge region of kinase. Chromen hete-
rocycle in this position is surrounded by hydrophobic
residues Leu484, Leu630, Phe489 and Ala512. Phenyl
radical enters the hydrophobic environment formed by
residues Ala640, Ile545 and Lys514, increasing the in-
hibitor affinity to FGFR1 [56]. The similar orientation
of flavonoid inhibitors is observed in the complexes of
other kinases – CDK6 and flavopiridol [62], PIM1 and
quercetagetin [63], phosphatidyl inositol kinase � and
quercetin [64].
The developed model of binding allowed us to assu-
me that hydrophobic groups in position 6 of chromenon
enter into energetically beneficial hydrophobic environ-
ment of side chains of aminoacid residues Leu484 and
Tyr563 in the active site. At the same time the methyl
substituent in position 7 does not have any hydropho-
bic environment in the enzyme pocket. The methyl sub-
stituent in position 8 is quite close to the side chain Phe
489 and can change the binding mode of the ligand with
kinase. Thus, the introduction of hydrophobic substi-
tuents into position 6 of chromen heterocycle increases
the affinity of flavonols to the kinase via hydrophobic
interactions, while hydrophobic substituents in positions
7 and 8 do not have a similar effect [56].
Oxyindoles have already been known as active in-
hibitors of tyrosine protein kinases. For instance, suni-
tinib was introduced into clinical practice in 2006 as a
multi-inhibitor of PTK and used to treat renal carci-
noma [65]. Oxyindole inhibitors are also known for
FGFR1 [66]. At the same time the search for active and
selective inhibitors of protein kinases among oxyin-
doles is in progress [67]. The highest activity towards
FGFR1 among the investigated derivatives of oxyin-
doles was demonstrated by (2-oxo-1,2-dihydroindole-
3-idine)-hydrazide-2-hydroxybenzoic acid. IC50 for this
compound is 1.25 µM [57].
The most efficient inhibitors of FGFR1 were reve-
aled among the representatives of quinazolines. High in-
hibitory activity towards FGFR1 was demonstrated by
compounds of subclass of 4-anilinoquinazolines. Con-
trary to compounds of other investigated classes, three
representatives of 4-anilinoquinazolines (ACH24,
ACH25 and ACH26) inhibit the activity of FGFR1 in
submicromolar concentrations [58]. It is noteworthy
that the derivatives of quinazolines are capable to inhibit
receptor tyrosine kinases EGFR [68] (gefitinib and er-
lotinib – EGFR inhibitors, used in the clinical practice
as anticancer drugs) and VGFR [69].
Inhibitors of protein kinase ASK1. ASK1 (apop-
tosis signal-regulating kinase 1) is a serine/threonine
protein kinase, involved in the control of differentia-
tion, aging, inflammatory processes and apoptosis, de-
pending on the type and redox status of cells as well as
on the development of immune response [70, 71]. The
increased activity of ASK1 is related to various disea-
ses – fibrous histiocytoma [72], gastric cancer [73], Alz-
heimer’s disease [74–76], amyotrophic lateral sclero-
sis [77], myocarditis, heart fibrosis and other cardiovas-
cular pathologies [78, 79]. Thus ASK1 inhibitors may
be used as drugs for treatment of oncological, neurode-
generative and cardiovascular diseases.
At present there are several communications on the
developed inhibitors of protein kinase ASK1. One class
of inhibitors of this enzyme is patented [80]. Recently
there has been an article of Japanese investigators on
the search for ASK1 inhibitors using the virtual scree-
ning technology [81], in which the authors managed to
find inhibitors only with IC50 in the range of 13–25 µM.
The technology of rational design was used (Voly-
nets et al.) to develop two new ATP-competitive clas-
ses of ASK1 protein kinase inhibitors – on the basis of
2-thioxo-thiazolidine-4-one derivatives and 3H-na-
phtho[1,2,3-de]quinoline-2,7-dione derivatives [82–
84]. Both classes were demonstrated to interact with
ATP-acceptor site of protein kinase ASK1 via common
structural mechanisms. The fixation of compounds in
ATP-binding pocket of ASK1 occurs due to hydropho-
bic interactions of inhibitors and amino acid residues
Leu686, Val694, Ala707, Met754, Val757, Val738 and
Leu810 as well as because of the formation of hydro-
gen bonds with the hinge and phosphate-binding site of
the enzyme.
Among the representatives of 2-thioxo-thiazolidi-
ne-4-ones, the highest activity was demonstrated by
344
YARMOLUK S. M., NYPORKO A. Yu., BDZHOLA V. G.
compound PFTA-1 – 2-{5-[5-(3,4-dichlorophenyl)-fu-
ran-2-ilmethylen]-4-oxo-2-thioxo-thiazolidine-3-yl}-
propanoic acid with submicromolar activity towards
ASK1 – IC50 is 650 nM, and Ki – 340 nM [83].
The inhibitor selectivity was investigated in the re-
action in vitro with protein kinases Aurora A, CK2,
JNK3, FGFR1, HGFR1, Tie2 and appropriate subst-
rates for each enzyme. The results demonstrated that
the inhibitor is specific to ASK1 except for the inhibi-
tory activity towards protein kinase Aurora A (the resi-
dual activity of protein kinase Aurora A after the intro-
duction of 10 µM of the inhibitor is 15 %). Thus, this
compound is promising for further optimization [83].
According to the results of structural analysis of the
interaction of PFTA-1 and ASK1 in silico and testing in
vitro, 5-(5-phenyl-furan-2-ylmethylen)-2-thioxo-thia-
zolidine-4-one, that is the structural basis for compound
PFTA-1, may serve as a pharmacophore for the design
of inhibitors of protein kinase ASK1. 32 new deriva-
tives of 5-(5-phenyl-furan-2-ylmethylen)-2-thioxothia-
zolidine-4-one were synthesized, 17 of them demonst-
rated inhibitory activity in submicromolar concentra-
tions. The most active ligands inhibit ASK1 with IC50 =
= 200–300 nM [82, 83].
Among derivatives of 3H-naphtho[1,2,3-de]quino-
line-2,7-diones the most active compound is ethyl 2,7-
dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-
carboxylate, called NQDI-1. It inhibits the activity of
protein kinase ASK1 with IC50 = 3000 and Ki = 500 nM
[84]. The selectivity of inhibitor NQDI-1 was investi-
gated in the reactions in vitro with protein kinases Auro-
ra A, CK2, JNK3, ROCK1, FGFR1, HGFR1, Tie2 and
specific substrates for each enzyme. The investigations
demonstrated that the inhibitor has specific activity to-
wards ASK1 [84].
Ñ. M. ßðìîëþê, Î. Þ. Íèïîðêî, Â. Ã. Áäæîëà
Ðàö³îíàëüíèé äèçàéí ³íã³á³òîð³â ïðîòå¿íê³íàç
Ðåçþìå
Ñó÷àñí³ ìåòîäîëîã³÷í³ ï³äõîäè äî ðàö³îíàëüíîãî äèçàéíó íèçüêî-
ìîëåêóëÿðíèõ ñïîëóê, ùî õàðàêòåðèçóþòüñÿ ñïåöèô³÷íîþ àê-
òèâí³ñòþ ùîäî çàäàíèõ á³îìîëåêóëÿðíèõ ì³øåíåé, ðîçãëÿíóòî íà
ïðèêëàä³ ðîçðîáêè âèñîêîåôåêòèâíèõ ³íã³á³òîð³â ïðîòå¿íê³íàç.
Âèñâ³òëåíî íîâ³ îá÷èñëþâàëüí³ ìåòîäè, çàñòîñóâàííÿ ÿêèõ äàº
çìîãó ñóòòºâî ïîêðàùèòè ÿê³ñòü êîìï’þòåðíèõ åêñïåðèìåíò³â
(çîêðåìà, òî÷í³ñòü ïåðåäáà÷åííÿ àêòèâíîñò³ íèçüêîìîëåêóëÿð-
íèõ ñïîëóê) áåç çá³ëüøåííÿ ðîçðàõóíêîâèõ ïîòóæíîñòåé òà âèò-
ðàòè ÷àñó. Åôåêòèâí³ñòü ñòðàòå㳿 ðàö³îíàëüíîãî äèçàéíó ï³ä-
òâåðäæåíî íèçêîþ âëàñíèõ äîñë³äæåíü ç ðîçðîáêè íîâèõ ³íã³á³òî-
ð³â ïðîòå¿íê³íàç ÑÊ2, FGFR1 ³ ASK1.
Êëþ÷îâ³ ñëîâà: ðàö³îíàëüíèé äèçàéí, ³íã³á³òîðè ïðîòå¿íê³íàç,
íèçüêîìîëåêóëÿðí³ ñïîëóêè, ïðîòå¿íê³íàçè ÑÊ2, FGFR1 ³ ASK1.
Ñ. Í. ßðìîëþê, À. Þ. Íûïîðêî, Â. Ã. Áäæîëà
Ðàöèîíàëüíûé äèçàéí èíãèáèòîðîâ ïðîòåèíêèíàç
Ðåçþìå
Ñîâðåìåííûå ìåòîäîëîãè÷åñêèå ïîäõîäû ê ðàöèîíàëüíîìó äèçàé-
íó íèçêîìîëåêóëÿðíûõ ñîåäèíåíèé, õàðàêòåðèçóþùèõñÿ ñïåöèôè-
÷åñêîé àêòèâíîñòüþ ïî îòíîøåíèþ ê çàäàííûì áèîìîëåêóëÿð-
íûì ìèøåíÿì, ðàññìîòðåíû íà ïðèìåðå ðàçðàáîòêè âûñîêîýô-
ôåêòèâíûõ èíãèáèòîðîâ ïðîòåèíêèíàç. Îñâåùåíû íîâûå âû÷èñ-
ëèòåëüíûå ìåòîäû, ïðèìåíåíèå êîòîðûõ äàåò âîçìîæíîñòü çíà-
÷èòåëüíî óëó÷øèòü êà÷åñòâî êîìïüþòåðíûõ ýêñïåðèìåíòíîâ (â
÷àñòíîñòè, òî÷íîñòü ïðåäñêàçàíèÿ àêòèâíîñòè íèçêîìîëåêó-
ëÿðíûõ ñîåäèíåíèé) áåç óâåëè÷åíèÿ ðàñ÷åòíûõ ìîùíîñòåé è çà-
òðàò âðåìåíè. Ýôôåêòèâíîñòü ñòðàòåãèè ðàöèîíàëüíîãî äèçàé-
íà ïîäòâåðæäåíà ðÿäîì ñîáñòâåííûõ èññëå- äîâàíèé ïî ñîçäà-
íèþ íîâûõ èíãèáèòîðîâ ïðîòåèíêèíàç ÑÊ2, FGFR1 è ASK1.
Êëþ÷åâûå ñëîâà: ðàöèîíàëüíûé äèçàéí, èíãèáèòîðû ïðîòåèí-
êèíàç, íèçêîìîëåêóëÿðíûå ñîåäèíåíèÿ, ïðîòåèíêèíàçû ÑÊ2, FGFR1
è ASK1.
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Received 01.04.13
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