Advances in structure-based drug discovery of carbonic anhydrase inhibitors

ABSTRACT

Introduction: The enzyme carbonic anhydrase (CA, EC 4.2.1.1) is found in numerous organisms across the tree of life, with seven distinct classes known to date. CA inhibition can be exploited for the treatment of edema, glaucoma, seizures, obesity, cancer and infectious diseases. A myriad of CA inhibitor (CAI) classes and inhibition mechanisms have been identified over the past decade, mainly through structure-based drug design approaches. Five different CA inhibition mechanisms are presently known.

Areas covered: Recent advances in structure-based CAI design are reviewed, with periodic table-based organization of inhibitor classes.

Expert opinion: Various structure-based drug design studies have led to deep understanding of factors governing tight binding and selectivity for the various isoforms. Carboxylic acids, phenols, polyamines, diols, borols, boronic acids, coumarins and sulfonamides represent successful stories which led to an anti-tumor sulfonamide in Phase I clinical trials (SLC-0111). For many inhibitor classes, no detailed crystallographic data are available. Detailed structural characterization of all CAI classes may lead to further advances in the field with potential therapeutic implications in the management of indications including neuropathic pain, cerebral ischemia, arthritis and tumor imaging.

KEYWORDS:

• Carbonic anhydrase
• inhibitor
• sulfonamide
• coumarin
• dithiocarbamate
• inhibition mechanism
• X-ray crystallography

Acknowledgments

I am very much grateful to all my collaborators, in Florence and elsewhere, for their wonderful enthusiasm and help in many projects which led to interesting discoveries in the CA field. I particularly thank Dr. Marta Ferraroni for help with some of the figures from the article.

Declaration of interest

CT Supuran is the author of several patents in the field of CA inhibitors. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

CT Supuran’s research has been financed by several EU projects Euroxy, Metoxia, DeZnIt and Dynano.