Small-Molecule Ligands as Potential GDNF Family Receptor Agonists

ACS Omega
Larisa IvanovaMati Karelson

Abstract

To find out potential GDNF family receptor α1 (GFRα1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRα1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity ≥ 80%). Five compounds from the ZINC library were tested in phosphorylation and luciferase assays to study their ability to activate GFRα1-RET. A bidental compound with two carboxyl groups showed the highest activity in molecular modeling and biological studies. However, the relative position of these groups was important. The meta-substituted structure otherwise identical to the most active compound 2-[4-(5-carboxy-1H-1,3-benzodiazol-2-yl)phenyl]-1H-1,3-benzodiazole-5-carboxylic acid was inactive. A weaker activity was detected for a compound with a single carboxyl group, that is, 4-(1,3-benzoxazol-2-yl)benzoic acid. The substitution of the carboxyl group by the amino or acetamido group also led to the loss of the activity.

References

May 4, 2002·Nature Reviews. Neuroscience·Matti S Airaksinen, Mart Saarma
Nov 21, 2002·Neurochemistry International·Kimiko TokugawaShigeru Okuyama
Oct 3, 2003·Chemistry & Biology·Amy C Anderson
Oct 7, 2003·Nature Medicine·Luis R GardellFrank Porreca
Mar 27, 2004·The EMBO Journal·Veli-Matti LeppänenAdrian Goldman
Oct 8, 2005·Journal of Computational Chemistry·Jay L BanksRonald M Levy
Jan 16, 2007·Trends in Pharmacological Sciences·Maxim M Bespalov, Mart Saarma
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
May 30, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Vimal Parkash, Adrian Goldman
Mar 31, 2010·Molecular and Cellular Neurosciences·Yulia A SidorovaMaxim M Bespalov
May 17, 2012·Journal of Chemical Information and Modeling·John J IrwinRyan G Coleman
Jun 12, 2012·Current Medicinal Chemistry·Polamarasetty AparoyPallu Reddanna
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Jan 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Kristian L HedstromGabriel Corfas
Dec 1, 2004·Drug Discovery Today. Technologies·Christopher A Lipinski
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Jul 16, 2015·Human Gene Therapy·Andrii DomanskyiMikko Airavaara
Feb 2, 2016·Neurobiology of Disease·Carlos F Ibáñez, Jaan-Olle Andressoo

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Citations

Sep 6, 2018·Current Neuropharmacology·Yulia A SidorovaNariman F Salakhutdinov
Oct 17, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Kana Hamada, Amy W Lasek
Aug 25, 2020·Cell and Tissue Research·Don Marshall GashJohn T Slevin
Sep 12, 2020·International Journal of Molecular Sciences·Yulia A Sidorova, Mart Saarma
Dec 29, 2020·Frontiers in Aging Neuroscience·Fredric P ManfredssonRonald J Mandel
May 25, 2021·Journal of Parkinson's Disease·Juho-Matti RenkoYulia A Sidorova
Nov 7, 2019·Journal of Chemical Information and Modeling·Xingye ChenYanmin Zhang

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Methods Mentioned

BETA
electron
X-ray
ELISA

Key Resources (RRID) Mentioned

AB_631316
AB_309678

Software Mentioned

HyperChem
Protein Preparation Wizard of Maestro
Simulation Interaction Diagram
Schrödinger
PathDetect
RESPA
AutoDockTools ( ADT )
MM
Vina
Visual Studio

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