2. Academic Validation
  3. Identification of a potent heme oxygenase-2 (HO-2) inhibitor by targeting the secondary hydrophobic pocket of the HO-2 western region

Identification of a potent heme oxygenase-2 (HO-2) inhibitor by targeting the secondary hydrophobic pocket of the HO-2 western region

  • Bioorg Chem. 2020 Nov;104:104310. doi: 10.1016/j.bioorg.2020.104310.
Giuseppe Floresta 1,  Antonino N Fallica 2,  Giuseppe Romeo 2,  Valeria Sorrenti 2,  Loredana Salerno 2,  Antonio Rescifina 2,  Valeria Pittalà 3
Affiliations

Affiliations

  • 1 Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy; Department of Analytics, Environmental & Forensics, King's College London, Stamford Street, London SE1 9NH, UK.
  • 2 Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.
  • 3 Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy. Electronic address: [email protected].
PMID: 33010625 DOI: 10.1016/j.bioorg.2020.104310
Abstract

The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds.

Keywords

Azalanstat; Heme oxygenase-1; Heme oxygenase-2; Imidazole derivatives; Structure-activity relationships; Western region.

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