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. 2023 Dec;38(1):2235089.
doi: 10.1080/14756366.2023.2235089.

Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives

Deepak Shilkar  1 , Mohd Usman Mohd Siddique  2 , Silvia Bua  3 , Sabina Yasmin  1   4 , Mrunali Patil  2 , Ajay Kumar Timiri  1 , Claudiu T Supuran  3 , Venkatesan Jayaprakash  1
Affiliations

Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives

Deepak Shilkar et al. J Enzyme Inhib Med Chem. 2023 Dec.

Abstract

A series of phthalimide-capped benzene sulphonamides (1-22) reported by our group for dengue protease inhibitory activity have been evaluated for their carbonic anhydrase (hCA, EC 4.2.1.1) inhibitory activity against hCA I, hCA II. Compounds 1, 3, 10, and 15 showed hCA I inhibition, whereas 1, 4, and 10 showed hCA II inhibition at nanomolar concentrations. Among these compounds, 1 displayed potent inhibitory activity against the hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM), being 10 and 6 times more potent than acetazolamide, a standard inhibitor (Ki = 250 nM and 12 nM), respectively. Furthermore, this compound displayed 14-fold selectivity towards the hCA II isoform compared to hCA I. Molecular docking and MD simulations were performed to understand the atomic level interactions responsible for the selectivity of compound 1 towards hCA II.

Keywords: Carbonic anhydrase; molecular docking; molecular dynamics; phthalyl sulphamoyl derivatives.

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Conflict of interest statement

All authors (except CTS) declare no conflict of interest. CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. 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
Figure 1.
Figure 1.
A 2D plot illustrating the interaction of ACTZ and compound 1 with human carbonic anhydrase II (PDB: 5E2M). The plot depicts the common interacting residues between the two ligands as red circles, hydrophobic interactions as arcs with red spikes, and H-bonding interactions as dashed green lines. The plot uses colour coding to distinguish between different atoms and bonds, with carbon atoms in black, oxygen atoms in red, nitrogen atoms in blue, sulphur atoms in yellow, and chloro atoms in green. The bonds of the amino acid residues are coloured brown, while the ligands are coloured violet. The zinc ion is presented in pink.
Figure 2.
Figure 2.
A 2D plot illustrating the interaction of ACTZ and compound 1 with human carbonic anhydrase II (PDB: 5MJN). The plot depicts the common interacting residues between the two ligands as red circles, hydrophobic interactions as arcs with red spikes, and H-bonding interactions as dashed green lines. The plot uses colour coding to distinguish between different atoms and bonds, with carbon atoms in black, oxygen atoms in red, nitrogen atoms in blue, sulphur atoms in yellow, and chloro atoms in green. The bonds of the amino acid residues are coloured brown, while the ligands are coloured violet. The zinc ion is presented in pink.
Figure 3.
Figure 3.
A 2D plot illustrating the interaction of ACTZ and compound 1 with AF-A0A1S4EX12 (AlphaFold structure). The plot depicts the common interacting residues between the two ligands as red circles, hydrophobic interactions as arcs with red spikes, and H-bonding interactions as dashed green lines. The plot uses colour coding to distinguish between different atoms and bonds, with carbon atoms in black, oxygen atoms in red, nitrogen atoms in blue, sulphur atoms in yellow, and chloro atoms in green. The bonds of the amino acid residues are coloured brown, while the ligands are coloured violet. The zinc ion is presented in pink.
Figure 4.
Figure 4.
The root mean square deviation plot of AlphaFold (black), hCA I (red), and hCA II (green) with compound 1.
Figure 5.
Figure 5.
The root mean square fluctuation plot of AlphaFold (black), hCA I (red), and hCA II (green) with compound 1.
Figure 6.
Figure 6.
The radius of gyration plot of AlphaFold (black), hCA I (red), and hCA II (green) with compound 1.
Figure 7.
Figure 7.
The solvent-accessible surface area plot of AlphaFold (black), hCA I (red), and hCA II (green) with compound 1.
Figure 8.
Figure 8.
The RMSD plot of ligand fit to protein backbone of AlphaFold (black), hCA I (red), and hCA II (green) with compound 1.
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