Exploring the multiple binding modes of inhibitors to carbonic anhydrases for novel drug discovery

ABSTRACT

Introduction

The spacious active site cavity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) shows a great versatility for a variety of binding modes for modulators of activity, inhibitors, and activators, some of which are clinically used drugs.

Areas covered

There are at least four well-documented CA inhibition mechanisms and the same number of binding modes for CA inhibitors (CAIs), one of which superposes with the binding of activators (CAAs). They include (i) coordination to the catalytic metal ion; (ii) anchoring to the water molecule coordinated to the metal ion; (iii) occlusion of the active site entrance; and (iv) binding outside the active site. A large number of chemical classes of CAIs show these binding modes explored in detail by kinetic, crystallographic, and other techniques. The tail approach was applied to all of them and allowed many classes of highly isoform-selective inhibitors. This is the subject of our review.

Expert opinion

All active site regions of CAs accommodate inhibitors to bind, which is reflected in very different inhibition profiles for such compounds and the possibility to design drugs with effective action and new applications, such as for the management of hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, and degenerative disorders.

KEYWORDS:

• Carbonic anhydrase
• inhibition mechanism
• inhibitor
• isoforms
• tail approach
• scaffold
• X-ray crystallography
• zinc-binding group

Article Highlights

• Carbonic anhydrases (CAs) are metabolic/pH regulating enzymes, which catalyze the interconversion between CO₂ and bicarbonate with formation of H⁺ ions.

• There are eight genetic CA families in organisms all over the phylogenetic tree, but only 15 α-CA isoforms are present in humans, 12 of which are catalytically active and drug targets.

• X-ray crystallography, kinetics and other biophysical studies allowed a deep understanding of the various CA inhibition mechanisms, of which four are presently known in detail.

• Many CA inhibitors act by binding to the metal ion from the enzyme active site, whereas other anchor to the water molecule coordinated to the metal ion.

• New classes of inhibitors show a very diverse mechanism, binding and occluding the entrance of the active site cavity or even binding outside the active site.

• The highly diverse binding regions to the human family of CAs allowed the design of many classes of highly isoform-selective inhibitors.

• New applications in fields not typically connected with CA inhibition, such as management of hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, and degenerative disorders were thus possible.

This box summarizes key points contained in the article.

Declaration of Interest

C Supuran is a co-author of 20 patents of carbonic anhydrase inhibitors, and of which includes the patent for anti-tumor agent SLC-0111. 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.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.