Discovery of New Potential Anti-Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target-Focused Repurposing Approaches.
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.
Università degli Studi di Parma, Dipartimento di Farmacia, P4T group, Parco Area delle Scienze, Via G.P. Usberti 27A, 43121, Parma, Italy.
Giannamaria
G
Annunziato
Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
Andrea
A
Angeli
Università degli Studi di Parma, Dipartimento di Farmacia, P4T group, Parco Area delle Scienze, Via G.P. Usberti 27A, 43121, Parma, Italy.
Francesca
F
D'Alba
Università degli Studi di Parma, Dipartimento di Farmacia, P4T group, Parco Area delle Scienze, Via G.P. Usberti 27A, 43121, Parma, Italy. agostino.bruno@unipr.it.
Agostino
A
Bruno
Università degli Studi di Parma, Dipartimento di Farmacia, P4T group, Parco Area delle Scienze, Via G.P. Usberti 27A, 43121, Parma, Italy.
Marco
M
Pieroni
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy.
Daniela
D
Vullo
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131, Napoli, Italy.
Viviana
V
De Luca
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131, Napoli, Italy.
Clemente
C
Capasso
Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. claudiu.supuran@unifi.it.|Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy. claudiu.supuran@unifi.it.
Claudiu T
CT
Supuran
Università degli Studi di Parma, Dipartimento di Farmacia, P4T group, Parco Area delle Scienze, Via G.P. Usberti 27A, 43121, Parma, Italy.
Gabriele
G
Costantino
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases
carbonic anhydrase; computational chemistry; drug design; enzymes; inhibitors