Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)

Alexander K H Weiss; Richard Wurzer; Patrycia Klapec; Manuel Philip Eder; Johannes R Loeffler; Susanne von Grafenstein; Stefania Monteleone; Klaus R Liedl; Pidder Jansen-Dürr; Hubert Gstach

doi:10.3390/molecules26165009

Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)

Molecules. 2021 Aug 18;26(16):5009. doi: 10.3390/molecules26165009.

Authors

Affiliations

¹ Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
² Department of Organic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, A-1090 Vienna, Austria.
³ Campus Tulln, University of Applied Sciences Wiener Neustadt, Konrad-Lorenz-Straße 10, A-3430 Tulln an der Donau, Austria.
⁴ Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria.
⁵ Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria.
⁶ Department of Pharmaceutical Sciences, Pharmaceutical Chemistry Division, Faculty of Life Sciences, University of Vienna, Althanstraße 14, UZ2 E349, A-1090 Vienna, Austria.

Abstract

FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC₅₀ range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1.

Keywords: FAHD1; ODx; enzyme inhibitor; mitochondria; oxaloacetate.

MeSH terms

Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Hydrolases / antagonists & inhibitors*
Hydrolases / chemistry
Hydrolases / metabolism
Molecular Docking Simulation
Protein Conformation

Substances

Enzyme Inhibitors
FAHD1 protein, human
Hydrolases

Abstract

MeSH terms

Substances

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