Multi-Armed 1,2,3-Selenadiazole and 1,2,3-Thiadiazole Benzene Derivatives as Novel Glyoxalase-I Inhibitors

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 18; p. 3210
• Main Authors: Al-Balas, Qosay A, Al-Smadi, Mousa L, Hassan, Mohammad A, Al Jabal, Ghazi A, Almaaytah, Ammar M, Alzoubi, Karem H
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04-09-2019; MDPI
• Subjects: 1,2,3-Selenadiazole; 1,2,3-Thiadiazole; Acetanilides - chemistry; Acetanilides - pharmacology; Benzene; Binding Sites; Cancer; Crystal structure; Design; Detoxification; Drug development; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Glyoxalase-I; Humans; Hydrocarbons; Hydrogen Bonding; Inhibition; Lactoylglutathione Lyase - antagonists & inhibitors; Lactoylglutathione Lyase - chemistry; Ligands; Metabolism; Metabolites; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Protein Binding; Proteins; Pyruvaldehyde; Selenium; Structure-Activity Relationship; Sulfur; Thiadiazoles; Zinc Binding Feature; United States > US; 1,2,3-Selenadiazole; Glyoxalase-I; Inhibition; 1,2,3-Thiadiazole; Zinc Binding Feature
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24183210

Glyoxalase-I (Glo-I) enzyme was established to be a valid target for anticancer drug design. It performs the essential detoxification step of harmful byproducts, especially methylglyoxal. A robust computer-aided drug design approach was used to design and validate a series of compounds with selenium or sulfur based heterorings. A series of in-house multi-armed 1,2,3-selenadiazole and 1,2,3-thiadiazole benzene derivatives were tested for their Glo-I inhibitory activity. Results showed that these compounds bind Glo-I active sites competitively with strong potential to inhibit this enzyme with IC
values in micro-molar concentration. Docking poses revealed that these compounds interact with the zinc atom at the bottom of the active site, which plays an essential role in its viability.