期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 29, 期 16, 页码 2197-2202出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.06.046
关键词
Cruzain (CRZ); Docking; MM-PBSA; Quinoxaline compounds; Cruzipain (CZ) inhibition assay
资金
- Universidad de Buenos Aires (UBA)
- Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET) grants (Argentina)
The binding of ten quinoxaline compounds (1-10) to a site adjacent to S2 (AS2) of cruzain (CRZ) was evaluated by a protocol that include a first analysis through docking experiments followed by a second analysis using the Molecular Mechanics-Poisson-Boltzmann Surface Area method (MM-PBSA). Through them we demonstrated that quinoxaline compounds bearing substituents of different sizes at positions 3 or 4 of the heterocyclic ring might interact with the AS2, particularly interesting site for drug design. These compounds showed docking scores (AGdock) which were similar to those estimated for inhibitors that bind to the enzyme through noncovalent interactions. Nevertheless, the free binding energies (AG) values estimated by MM-PBSA indicated that the derivatives 8-10, which bear bulky substituents at position 3 of the heterocycle ring, became detached from the binding site under a dynamic study. Surprisingly, the evaluation of the inhibitory activity of cruzipain (CZ) of some derivatives showed that they increase the enzymatic activity. These results lead us to conclude about the relevance of AS2 as a pocket for compounds binding site, but not necessarily for the design of anti-chagasic compounds.
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