Drug-resistant Neisseria gonorrhoeae is a critical threat to public health, and bacterial carbonic anhydrases expressed by N. gonorrhoeae are potential new therapeutic targets to combat this pathogen. To further expand upon our recent reports of bacterial carbonic anhydrase inhibitors for the treatment of N. gonorrhoeae, our team has solved ligand-bound crystal structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide, along with three analogs, in complex with the essential alpha-carbonic anhydrase isoform from N. gonorrhoeae. The structural data for the analogs presented bound to N. gonorrhoeae alpha-carbonic anhydrase supports the observed structure-activity relationship for in vitro inhibition with this scaffold against the enzyme. Moreover, the ligand-bound structures indicate differences in binding poses compared to those traditionally observed with the close human ortholog carbonic anhydrase II. These results present key differences in inhibitor binding between N. gonorrhoeae alpha-carbonic anhydrase and the human carbonic anhydrase II isoform.

Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to Neisseria gonorrhoeae α-Carbonic Anhydrase / Marapaka, Anil Kumar; Nocentini, Alessio; Youse, Molly S; An, Weiwei; Holly, Katrina J; Das, Chittaranjan; Yadav, Ravi; Seleem, Mohamed N; Supuran, Claudiu T; Flaherty, Daniel P. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - ELETTRONICO. - 14:(2023), pp. 103-109. [10.1021/acsmedchemlett.2c00471]

Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to Neisseria gonorrhoeae α-Carbonic Anhydrase

Nocentini, Alessio;Supuran, Claudiu T;
2023

Abstract

Drug-resistant Neisseria gonorrhoeae is a critical threat to public health, and bacterial carbonic anhydrases expressed by N. gonorrhoeae are potential new therapeutic targets to combat this pathogen. To further expand upon our recent reports of bacterial carbonic anhydrase inhibitors for the treatment of N. gonorrhoeae, our team has solved ligand-bound crystal structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide, along with three analogs, in complex with the essential alpha-carbonic anhydrase isoform from N. gonorrhoeae. The structural data for the analogs presented bound to N. gonorrhoeae alpha-carbonic anhydrase supports the observed structure-activity relationship for in vitro inhibition with this scaffold against the enzyme. Moreover, the ligand-bound structures indicate differences in binding poses compared to those traditionally observed with the close human ortholog carbonic anhydrase II. These results present key differences in inhibitor binding between N. gonorrhoeae alpha-carbonic anhydrase and the human carbonic anhydrase II isoform.
2023
14
103
109
Marapaka, Anil Kumar; Nocentini, Alessio; Youse, Molly S; An, Weiwei; Holly, Katrina J; Das, Chittaranjan; Yadav, Ravi; Seleem, Mohamed N; Supuran, Claudiu T; Flaherty, Daniel P
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1302900
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