Discovery of New Potential Anti‐Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target‐Focused Repurposing Approaches

Abstract

In academia, compound recycling represents an alternative drug discovery strategy to identify new pharmaceutical targets from a library of chemical compounds available in house. Herein we report the application of a rational target‐based drug‐repurposing approach to find diverse applications for our in‐house collection of compounds. The carbonic anhydrase (CA, EC 4.2.1.1) metalloenzyme superfamily was identified as a potential target of our compounds. The combination of a thoroughly validated docking screening protocol, together with in vitro assays against various CA families and isoforms, allowed us to identify two unprecedented chemotypes as CA inhibitors. The identified compounds have the capacity to preferentially bind pathogenic (bacterial/protozoan) CAs over human isoforms and represent excellent hits for further optimization in hit‐to‐lead campaigns.

Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target

“…A serious problem associated with periodontitis is that the polymicrobial community is usually resistant to antimicrobial agents and host-defense mechanisms. In this context, we investigated the possibility of finding new anti-infectives by studying the inhibition profiles of carbonic anhydrases (CAs, EC 4.2.1.1), a superfamily of metalloenzymes which catalyze the simple but physiologically crucial reaction of carbon dioxide hydration to bicarbonate and protons: CO 2 + H 2 O ⇄ HCO 3 − + H + [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Moreover, most studies concerning the treatment of periodontitis have primarily take into account the Gram-negative bacterium Porphyromonas gingivalis because it is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium [ 2 ].…”

Carbonic anhydrase IX as a novel candidate in liquid biopsy

“…Moreover, the interconversion of CO 2 and HCO 3 À is spontaneously and precisely balanced form the living organisms to maintain the equilibrium between dissolved inorganic carbon dioxide (CO 2 ), carbonic acid (H 2 CO 3 ), bicarbonate (HCO 3 À ) and carbonate (CO 3 2À ) [3][4][5][6] . The CO 2 hydration/dehydration is catalysed by a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1) [7][8][9][10][11] , which are categorised into eight genetically distinct families (or classes), named with the Greek letters: a, b, c, d, f, g, Õ, and i. The last three classes were recently discovered [12][13][14] .…”

Phaeodactylum tricornutum as a model organism for testing the membrane penetrability of sulphonamide carbonic anhydrase inhibitors

“…The physiologic/biosynthetic processes requiring CO 2 or HCO À 3 (respiration, photosynthesis/gluconeogenesis, lipogenesis, ureagenesis, carboxylation) and biochemical pathways involving pH homeostasis, secretion of electrolytes, calcification, bone resorption, transport of CO 2 , and bicarbonate, etc., are connected with the interconversion of CO 2 to bicarbonate and protons (CO 2 þ H 2 O HCO À 3 þ H þ ) 1,2 . In all living organism, the CO 2 hydration/ dehydration reaction is catalysed by a superfamily of ubiquitous metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1) [3][4][5][6][7][8][9][10] , which catalyse these reactions at very high rates, with a pseudo-first order kinetic constant (k cat ) ranging from 10 4 to 10 6 s À1 for the CO 2 hydration 11,12 . At the intracellular concentrations of CO 2 , the uncatalysed CO 2 hydration/dehydration reaction has a too low rate with an effective k cat of 0.15 s À1 for the hydration reaction, and a rate constant of 50 s À1 for the reverse reaction 11,12 .…”