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A novel sulfamethoxazole derivative as an inhibitory agent against HSP70: A combination of computational with in vitro studies

Authors :
Vaha Akbary Moghaddam
Asadollah Mohammadi
Omid Saberi
Vesal Kasmaeifar
Zainab Mahmoodi
Hossein Ghafouri
Source :
International Journal of Biological Macromolecules. 189:194-205
Publication Year :
2021
Publisher :
Elsevier BV, 2021.

Abstract

In the current study, a novel derivative of sulfamethoxazole (a sulfonamide containing anti-biotic) named ZM-093 (IUPAC name: (E)-4-((4-(bis(2-hydroxyethyl)amino)phenyl)diazenyl)-N-(5-methylisoxazole-3-yl)benzenesulfonamide) was synthesized via common diazotization-coupling reactions from sulfamethoxazole and subsequently characterized through NMR/FT-IR spectroscopy. After evaluation, the compound was geometrically optimized at the DFT level of theory with BL3YP method and 6/31++G (d,p) basis set and from the optimized structure, several molecular descriptors important in the biological reactivity of the compound, such as global reactivity parameters, molecular electrostatic potential, average local ionization energy, and drug-likeness features of the compound were computationally analyzed. The experimental in vitro investigations of the interaction between ZM-093 and heat shock protein 70 (HSP70), a protein that is highly expressed in several types of cancers, exhibited a significant inhibitory effect against the chaperone activity of HSP70 for the titled compound (P-value < 0.01) and the comparison between the experimental studies with the mentioned computational analysis, as well as molecular docking, illustrated that ZM-093 may inhibit HSP70 through binding to its substrate-binding domain. Finally, by taking all the previous results into account, a new method for assessing the inhibitory activity of ligand to HSP70 is introduced based on protonography, a recently developed method that is dependent on the catalytic activity of carbonic anhydrase on polyacrylamide gel electrophoresis.

Details

ISSN :
01418130
Volume :
189
Database :
OpenAIRE
Journal :
International Journal of Biological Macromolecules
Accession number :
edsair.doi.dedup.....22c32a78877f5622a7c5c9501cdc5140
Full Text :
https://doi.org/10.1016/j.ijbiomac.2021.08.128