Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors

• Published in: Journal of medicine and life 2024-01, Vol.17 (1), p.87-98
• Main Authors: Al-Akeedi, Mohammed, Najdawi, Manal, Al-Balas, Qosay, Al-Qazzan, Mohammed Bashar, Telfah, Soha Taher
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amides - pharmacology; Amino acids; Anthraquinone; Anthraquinones - chemistry; Anthraquinones - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding sites; Cancer; Crystal structure; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Fourier transforms; Humans; Lactoylglutathione Lyase - antagonists & inhibitors; Lactoylglutathione Lyase - metabolism; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Mortality; Original; Pharmacy; Proteins; Protocol; Simulation; Software; Structure-Activity Relationship
• ISSN: 1844-122X; 1844-3117; 1844-3117
• DOI: 10.25122/jml-2023-0257

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.