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. 2021 Dec;36(1):2118-2127.
doi: 10.1080/14756366.2021.1982933.

Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII. The out of the active site pocket for the design of selective inhibitors?

Leonardo E Riafrecha  1 , Macarena S Le Pors  1 , Martín J Lavecchia  2 , Silvia Bua  3 , Claudiu T Supuran  3   4 , Pedro A Colinas  1
Affiliations

Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII. The out of the active site pocket for the design of selective inhibitors?

Leonardo E Riafrecha et al. J Enzyme Inhib Med Chem. 2021 Dec.

Abstract

New C-glycosides and α,β-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.

Keywords: Vanillin; carbonic anhydrase; enones; enzyme inhibitors; molecular docking.

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Conflict of interest statement

CT Supuran is Editor-in-Chief of Journal of Enzyme Inhibition and Medicinal Chemistry and he was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

None
Graphical abstract
Scheme 1.
Scheme 1.
Preparation of vanillin enones 1–7 discussed in the paper
Figure 1.
Figure 1.
Structure of compounds 1–7.
Figure 2.
Figure 2.
Binding poses of 7 to four CA isozymes obtained through molecular docking using Smina program. The ligand poses can be seen inside the catalytic site. In addition, some poses show the inhibitor bound in the adjacent pocket (oriented to the left) to the entrance at the active site cavity in the case of isoforms CA I, II, and XII.
Figure 3.
Figure 3.
Per-residue decomposition of binding energy (only the enthalpy term considered) of ligand-bound hCA I and II, located in the pocket adjacent to the catalytic site. These calculations were performed with the MMPBSA.py module and plotted using Python's Matplotlib library. The residues shown were those that evidenced at least one interaction of < 0.3 kcal mol−1 with a ligand.
Figure 4.
Figure 4.
Poses of compound 7 bound in the adjacent pocket to the active site entrance of hCA I (above) and hCA II (below). Hydrogen bonds with residues Lys170, Pro 240, and Gln242 are highlighted in yellow. Images were generated with Pymol. The selected structures of all ligands with CAs are presented in the Supplementary Material.
See this image and copyright information in PMC

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