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

Giorgio Maccari; Davide Deodato; Diego Fiorucci; Francesco Orofino; Giuseppina I Truglio; Carolina Pasero; Riccardo Martini; Filomena De Luca; Jean-Denis Docquier; Maurizio Botta

doi:10.1016/j.bmcl.2017.06.016

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

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3332-3336. doi: 10.1016/j.bmcl.2017.06.016. Epub 2017 Jun 10.

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
² Department of Medical Biotechnology, University of Siena, I-53100 Siena, Italy.
³ Department of Medical Biotechnology, University of Siena, I-53100 Siena, Italy; Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
⁴ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA; Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy. Electronic address: botta.maurizio@gmail.com.

PMID: 28610983
DOI: 10.1016/j.bmcl.2017.06.016

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.

Keywords: Amidinoureas; Antifungal agents; Candida strains; Chitinase; Macrocyclic compounds; Target fishing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Chitinases / antagonists & inhibitors*
Chitinases / metabolism
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Trichoderma / drug effects*
Trichoderma / enzymology

Substances

Antifungal Agents
Enzyme Inhibitors
Chitinases