Chem Biol Drug Des 2016; 88: 54–65
Research Letter
General Ser/Thr Kinases Pharmacophore Approach for
Selective Kinase Inhibitors Search as Exemplified by
Design of Potent and Selective Aurora A Inhibitors
devoted to selected kinase of serine–threonine family, but
we surmised that there are a number of common features
of all serine–threonine inhibitors so it would be possible to
Natalya I. Vasilevich*, Elena A. Aksenova,
Denis N. Kazyulkin and Ilya I. Afanasyev
construct
a
general pharmacophore model which
Novie Nauchnie Tekhnologii Ltd. (ASINEX Company
Group), 20 Geroev Panfilovtsev Str., Moscow 125480,
Russia
*Corresponding author: Natalya I. Vasilevich,
subsequently could be optimized for specific kinds of
serine–threonine kinase.
To achieve our goal, we analysed a number of known inhi-
bitors of various serine–threonine kinases including com-
pounds, which have been found both in our laboratory
previously and in literature references cited above. For this
purpose, we used pharmacophore elucidating functionality
of MOE version 2010.10. The results of this work are on
Figure 1.
A general pharmachophore model for various types of
Ser/Thr kinases was developed. Search for the mole-
cules fitting to this pharmacophore among ASINEX
proprietary library revealed a number of compounds,
which were tested and appeared to possess some
activity against several Ser/Thr kinases such as Aurora
A, Aurora B and Haspin. The possibility of performing
the fine-tuning of the general Ser/Thr pharmacophore
to desired types of kinase to get active and selective
inhibitors was exemplified by Aurora A kinase. As a
result, several hits in 3–5 nM range of activity against
Aurora A kinase with rather good selectivity and ADME
properties were obtained.
As it is seen from the figure, the general pharmacophore
looks like a kind of diamond with two opposite hydropho-
bic centres, one aromatic centre and a couple of H-bond
donor and acceptor projections in one corner. The length
of a rhomb side is about 4–5 A.
Application of the general pharmacophore found to ASINEX
proprietary library allowed to identify a scaffold including
two 5- and 6-member heterocyclic aromatic rings linked
through NH group, containing additional pyrrolidine or
piperidine group attached to 6-member ring in meta-
position to NH group. To confirm their activity against Ser/
Thr kinases, a set of compounds belonging to this scaffold
was tested against Aurora A, Aurora B and Haspin kinases.
Key words: kinase, molecular modeling, pharmacophore
modeling, phosphatase, structure-based drug design
Received 8 October 2015, revised 29 December 2015 and
accepted for publication 7 January 2016
Serine–threonine kinases play an important role in signal
transduction pathways in both eukaryotic and prokaryotic
cells; they act in regulation of cell proliferation,
programmed cell death (apoptosis), cell differentiation and
embryonic development. Therefore, inhibitors of Ser/Thr
kinase activity have a broad range of potential therapeutic
uses – from treating cancer to promoting a desired
immunosuppressive effect. As these kinases were found in
a number of mycobacterial organisms, their inhibitors can
be attractive targets to treat bacterial infection (1).
A number of attempts have been done to construct a
pharmacophore model for various serine–threonine kinase
inhibitors. For example, pharmacophore for STPK inhibi-
tors of tuberculosis (2,3), for mTor kinase inhibitors (4), for
Aurora B inhibitors (5), for Aurora A inhibitors (6,7) and for
B-Raf inhibitors (8) was developed. All these works were
Figure 1: General pharmacophore of serine–threonine kinase
inhibitors (MOE 2010.10).
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ª 2016 John Wiley & Sons A/S. doi: 10.1111/cbdd.12733