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

被引：46

作者：

Annunziato, Giannamaria ^{[1
]}

Angeli, Andrea ^{[2
]}

D'Alba, Francesca ^{[1
]}

Bruno, Agostino ^{[1
]}

Pieroni, Marco ^{[1
]}

Vullo, Daniela ^{[3
]}

De Luca, Viviana ^{[4
]}

Capasso, Clemente ^{[4
]}

Supuran, Claudiu T. ^{[2
,3
]}

Costantino, Gabriele ^{[1
]}

机构：

[1] Univ Parma, Dipartimento Farm, Grp P4T, Parco Area Sci,Via GP Usberti 27A, I-43121 Parma, Italy

[2] Univ Florence, Neurofarba Dept, Sect Pharmaceut & Nutriceut Sci, Via U Schiff 6, I-50019 Florence, Italy

[3] Univ Florence, Polo Sci, Lab Chim Bioinorgan, Rm 188,Via Lastruccia 3, I-50019 Florence, Italy

[4] CNR, Ist Biosci & Biorisorse, Via Pietro Castellino 111, I-80131 Naples, Italy

来源：

CHEMMEDCHEM | 2016年 / 11卷 / 17期

关键词：

carbonic anhydrase; computational chemistry; drug design; enzymes; inhibitors; O-ACETYLSERINE SULFHYDRYLASE; PLASMODIUM-FALCIPARUM; MYCOBACTERIUM-TUBERCULOSIS; CARBOXYLIC-ACIDS; DESIGN; SULFONAMIDES; MOLECULE; BINDING; AGENTS; DRUGS;

D O I：

10.1002/cmdc.201600180

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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, EC4.2.1.1) metalloenzyme superfamily was identified as a potential target of our compounds. The combination of a thoroughly validated docking screening protocol, together with invitro 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.

引用

页码：1904 / 1914

页数：11

共 38 条

[1]

Ligand efficiency indices as guideposts for drug discovery [J].