Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Alessio Nocentini; Alessandro Bonardi; Paola Gratteri; Bruno Cerra; Antimo Gioiello; Claudiu T Supuran

doi:10.1080/14756366.2018.1512597

Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1453-1459. doi: 10.1080/14756366.2018.1512597.

Authors

Alessio Nocentini^{1

2}, Alessandro Bonardi^{1

2}, Paola Gratteri¹, Bruno Cerra³, Antimo Gioiello³, Claudiu T Supuran²

Affiliations

¹ a Department NEUROFARBA - Pharmaceutical and nutraceutical section; Laboratory of Molecular Modeling Cheminformatics & QSAR , University of Firenze , Sesto Fiorentino , Italy.
² b Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section , University of Florence , Firenze , Italy.
³ c Department of Pharmaceutical Sciences , University of Perugia , Perugia , Italy.

Abstract

Bile acids have been shown to inhibit human (h) carbonic anhydrases (CA, EC 4.2.1.1) along the gastrointestinal tract, including hCA II. The elucidation of the hormonal inhibition mechanism of the bile acid cholate to hCA II was provided in 2014 by X-ray crystallography. Herein, we extend the inhibition study to a wealth of steroids against four relevant hCA isoforms. Steroids displaying pendants and functional groups of the carboxylate, phenolic or sulfonate types appended at the tetracyclic ring were shown to inhibit the cytosolic CA II and the tumor-associated, transmembrane CA IX in a medium micromolar range (38.9-89.9 µM). Docking studies displayed the different chemotypes CA inhibition mechanisms. Molecular dynamics (MD) gave insights on the stability over time of hyocholic acid binding to CA II.

Keywords: Carbonic anhydrase; bile acid; inhibitor; phenol; steroids.

MeSH terms

Binding Sites
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases / classification
Carbonic Anhydrases / metabolism*
Computer Simulation
Deoxycholic Acid / chemistry
Deoxycholic Acid / metabolism
Drug Stability
Enzyme Activation / physiology
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Isoforms / chemistry
Steroids / chemistry
Steroids / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Protein Isoforms
Steroids
Deoxycholic Acid
hyodeoxycholic acid
Carbonic Anhydrases

Grants and funding

Ente Cassa di Risparmio di Firenze, Italy, is gratefully acknowledged for a grant to A.N (ECR 2016.0774). The Ph.D. fellowship for A.B was funded by University of Florence.