Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein
| Autor: | Liliane O. Ortlieb, Ícaro P. Caruso, Nathane C. Mebus-Antunes, Andrea T. Da Poian, Elaine da C. Petronilho, José Daniel Figueroa-Villar, Claudia J. Nascimento, Fabio C. L. Almeida |
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| Přispěvatelé: | Military Institute of Engineering (IME), Universidade Federal do Rio de Janeiro (UFRJ), Universidade Estadual Paulista (UNESP), Federal University of the State of Rio de Janeiro (UNIRIO) |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Dose-Response Relationship Drug Molecular Structure Hydrazones RM1-950 General Medicine Microbial Sensitivity Tests Dengue Virus Antiviral Agents Dengue virus NMR Structure-Activity Relationship drug-ligand interaction Drug Discovery Oximes Capsid Proteins Therapeutics. Pharmacology fluorescence Hydrophobic and Hydrophilic Interactions DENVC Research Article Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 287-298 (2022) Scopus Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP |
| ISSN: | 1475-6374 |
| Popis: | Made available in DSpace on 2022-04-29T08:37:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 We synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC. Department of Chemistry Military Institute of Engineering (IME) Institute of Medical Biochemistry Leopoldo de Meis (IBqM) and National Center for Structural Biology and Bioimaging (CENABIO) Federal University of Rio de Janeiro (UFRJ) Multiuser Center for Biomolecular Innovation (CMIB) and Department of Physics Institute of Biosciences Letters and Exact Sciences (IBILCE) São Paulo State University (UNESP) Institute of Medical Biochemistry Leopoldo de Meis (IBqM) Federal University of Rio de Janeiro (UFRJ) Department of Natural Sciences Institute of Biosciences Federal University of the State of Rio de Janeiro (UNIRIO) Multiuser Center for Biomolecular Innovation (CMIB) and Department of Physics Institute of Biosciences Letters and Exact Sciences (IBILCE) São Paulo State University (UNESP) |
| Databáze: | OpenAIRE |
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