Pharmacophore model design of maleimide derivatives as GSK-3β ATPCompetitive Inhibitors: A SBDD and LBDD approach
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CAMPOS, A.B.*
; CHAVEZ, S.M.
; YATACO, L.M.
; FERNANDES, V.M. ; GATTI, F. ;
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MALTAROLLO, V.G. *Author correspondence: schavezpacheco@gmail.com
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Bioinformatics and Pharmacogenetics Laboratory (BIOPHARM), Department of Biochemistry-Faculty of Pharmacy and
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Biochemistry, UNMSM; Department of Pharmacy - School of Pharmaceutical Sciences, USP; Department of Clinical
and Toxicological Analysis – School of Pharmaceutical Sciences, USP.
Keywords: SBDD, LBDD, pharmacophore, Glycogen synthase kinase 3β, maleimides
Introduction
The increase and accumulation of misfolding
proteins
is
one
of
the
hallmarks
of
neurodegenerative diseases such as Alzheimer and
Parkinson Disease. In spite of this knowledge, the
only drugs that were developed palliate the grade of
the symptoms without any effect on the disease
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progression . The glycogen synthase kinase 3
(GSK-3 ) may play a key role in the formation of the
neurofibrilar tangles responsible for the cellular
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death of the neurons . The search for new
therapeutic drug targets highlighted the GSK-3
relevance for the rational drug design. In this way,
we aimed to construct a pharmacophoric model
through SBDD and LBDD approaches of GSK-3β
ATP-competitive inhibitors derived from the
maleimide family.
Results and Discussion
PDB Structures 1R0E, 1Q4L and 2OW3 presented a
GSK-3 co-crystallized with a maleimide derived
compound; all characterized at resolutions lower
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than 2.8Å. According to Palomo et al. , the
aminoacids of the GSK-3
first pocket were
identified: residues Lys85-Glu97-Tyr134-Val135Thr138-Asn186-Cys199-Asp200. In these three
crystals, the carboxi and aminoterminal residues of
Asp133-Val135 presented common hydrogen bonds
with different heteroatoms of the maleimide ring. The
additional aromatic rings in the 1R0E and 1Q4L
crystals showed hydrophobic interactions with Val70
and unusual interactions with Ile62 (1R0E) and
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Cys199 (1Q4L). In 2014, Crisan et al. states the
essential interactions with residues Asp133-Val135Gln185-Cys199 to achieve great potency in this
group of inhibitors. It’s crucial to stand out that the
last two interactions give higher selectivity for the
beta isoform of GSK rather than for other kinases
phylogenetically related.
Figure 1. Interactions observed in 1Q4L and
1R0E
Conclusions
Based on the crystallographic data, the developed
pharmacophoric model showed 3 pharmacophoric
points: Donator and acceptor hydrogen bond and
aromatic ring. Out of 13 interactions identified, six
were with hydrogen acceptors, two were hydrogen
donators and last five were aromatic rings. As a
future purpose, lead optimization remains as the
ultimate goal to obtain more potent and selective
molecules in the neurodegenerative disease’s field.
Acknowledgements
This project was the collaborative effort of an
undergraduate team under guide of graduated
students, Fernando de Moura Gatti and Vinícius G.
Maltarollo, and Professor Gustavo H. Trossini,
whose are convinced that research in rational drug
design is the appropriated path to obtain new
druggable candidates. The team is infinitely pleased
to Professor Trossini for the guide, tutoring and
patience with us throughout the development of this
project made in the undergraduate course:
Advanced Drug Design (FBF0348).
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SHINEMAN, D. et al. BMC Neurol. 2009, v. 9(S1:I1).
STEINMETZ, K. L. et al. BMC Neurol .2009, v. 9(S1:S2).
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MARTINEZ, A. et al. J Alzheimer Disease. 2008, v. 15, p. 181191.
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PALOMO, V. et al. J Med Chem. 2011, v. 52, p. 8461-8470.
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CRISAN, L. et al. J Enzyme Inhib Med Chem. 2014, v. 29, p.
599-610.
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