Article (Scientific journals)
Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol
Maccari, G.; Deodato, D.; Fiorucci, D. et al.
2017In Bioorganic and Medicinal Chemistry Letters, 27 (15), p. 3332-3336
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Keywords :
Amidinoureas; Antifungal agents; Candida strains; Chitinase; Macrocyclic compounds; Target fishing; Article; Trichoderma viride; Trichoderma; Chitinases; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Structure-Activity Relationship
Abstract :
[en] 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. © 2017 Elsevier Ltd
Disciplines :
Life sciences: Multidisciplinary, general & others
Biochemistry, biophysics & molecular biology
Microbiology
Author, co-author :
Maccari, G.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Deodato, D.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Fiorucci, D.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Orofino, F.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Truglio, G. I.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Pasero, C.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Martini, R.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
De Luca, F.;  Department of Medical Biotechnology, University of Siena, Siena, I-53100, Italy
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Botta, M.;  Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, I-53100, 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, United States, Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, Castelnuovo Berardenga, I-53019, Italy
Language :
English
Title :
Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol
Publication date :
2017
Journal title :
Bioorganic and Medicinal Chemistry Letters
ISSN :
0960-894X
eISSN :
1464-3405
Publisher :
Elsevier Ltd
Volume :
27
Issue :
15
Pages :
3332-3336
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 19 November 2020

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