Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds
| Autor: | Carlos A. Montanari, Rafael da Fonseca Lameiro, Fabiana Rosini, Rodrigo Cendron, Pedro Henrique Jatai Batista, Anwar Shamim |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Chagas disease Nitrile Molecular model Cathepsin L Leishmania mexicana Protozoan Proteins Cysteine Proteinase Inhibitors 01 natural sciences LEISHMANIA MEXICANA Structure-Activity Relationship chemistry.chemical_compound Block (telecommunications) Nitriles 0103 physical sciences Drug Discovery medicine Humans Chagas Disease Leishmaniasis Pharmacology 010304 chemical physics biology Chemistry Fluorine medicine.disease Combinatorial chemistry 0104 chemical sciences Cysteine Endopeptidases 010404 medicinal & biomolecular chemistry biology.protein Thermodynamics Molecular Medicine |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1756-8927 1756-8919 |
| Popis: | Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials & methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy. |
| Databáze: | OpenAIRE |
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