Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol

Author(s)
Giorgio Maccari, Davide Deodato, Diego Fiorucci, Francesco Orofino, Giuseppina I Truglio, Carolina Pasero, Riccardo Martini, Filomena De Luca, Jean-Denis Docquier, Maurizio Botta
Abstract

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.

Organisation(s)
Journal
Bioorganic & Medicinal Chemistry Letters
Volume
27
Pages
3332-3336
No. of pages
5
ISSN
0960-894X
DOI
https://doi.org/10.1016/j.bmcl.2017.06.016
Publication date
08-2017
Publication status
Published
Peer reviewed
Yes
Austrian Fields of Science 2012
301207 Pharmaceutical chemistry
Keywords
Antifungal Agents/chemical synthesis, Chitinases/antagonists & inhibitors, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors/chemical synthesis, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Trichoderma/drug effects
Portal url
https://ucris.univie.ac.at/portal/en/publications/design-and-synthesis-of-a-novel-inhibitor-of-t-viride-chitinase-through-an-in-silico-target-fishing-protocol(9d0835eb-2d20-4b0c-a1a6-1788e5aeba31).html