Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors

Acta Crystallographica. Section D, Biological Crystallography
Manuel EllermannMarkus G Rudolph

Abstract

The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.1.6) inactivates neurotransmitters by catalyzing the transfer of a methyl group from S-adenosylmethionine to catechols in the presence of Mg²⁺. This pathway also inactivates L-DOPA, the standard therapeutic for Parkinson's disease. Depletion of catechol neurotransmitters in the prefrontal cortex has been linked to schizophrenia. The inhibition of COMT therefore promises improvements in the treatment of these diseases. The concept of bisubstrate inhibitors for COMT has been described previously. Here, ribose-modified bisubstrate inhibitors were studied. Three high-resolution crystal structures of COMT in complex with novel ribose-modified bisubstrate inhibitors confirmed the predicted binding mode but displayed subtle alterations at the ribose-binding site. The high affinity of the inhibitors can be convincingly rationalized from the structures, which document the possibility of removing and/or replacing the ribose 3'-hydroxyl group and provide a framework for further inhibitor design.

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Citations

Jan 30, 2015·Angewandte Chemie·Elke PerschFrançois Diederich
May 30, 2013·British Journal of Clinical Pharmacology·Zhiguo MaBaojian Wu
Aug 2, 2014·Acta Crystallographica. Section D, Biological Crystallography·Andreas EhlerMarkus G Rudolph
Nov 5, 2016·The Journal of Physical Chemistry. B·Heather J KulikTodd J Martínez
Mar 31, 2015·ACS Medicinal Chemistry Letters·Scott T HarrisonJames C Barrow
Sep 8, 2018·Chemical Reviews·Allie Y ChenSeth M Cohen
Aug 1, 2014·Journal of Medicinal Chemistry·László E Kiss, Patrício Soares-da-Silva
Oct 8, 2013·Journal of the American Chemical Society·Scott HorowitzRaymond C Trievel
Mar 16, 2019·Journal of Chemical Information and Modeling·Helena W Qi, Heather J Kulik
Aug 15, 2018·Journal of Chemical Information and Modeling·Vishal B SiramshettyBjoern-Oliver Gohlke
Oct 3, 2018·Journal of Medicinal Chemistry·Ingrid BuchlerJames C Barrow

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