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Discovery of New Potential Anti‐Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target‐Focused Repurposing Approaches
Author(s) -
Annunziato Giannamaria,
Angeli Andrea,
D'Alba Francesca,
Bruno Agostino,
Pieroni Marco,
Vullo Daniela,
De Luca Viviana,
Capasso Clemente,
Supuran Claudiu T.,
Costantino Gabriele
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600180
Subject(s) - drug repositioning , drug discovery , repurposing , carbonic anhydrase , computational biology , carbonic anhydrase ii , gene isoform , drug target , virtual screening , chemical library , chemistry , docking (animal) , drug , drug development , biochemistry , drug design , rational design , enzyme , combinatorial chemistry , biology , small molecule , pharmacology , medicine , genetics , gene , ecology , nursing
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.