Molecular docking and dynamic studies of a potential therapeutic target inhibiting glyoxalase system: Metabolic action of the 3, 3 '- [3- (5-chloro-2-hydroxyphenyl) -3-oxopropane-1, 1-diyl] - Bis-4-hydroxycoumarin leads overexpression of the intracellular level of methylglyoxal and induction of a pro-apoptotic phenomenon in a hepatocellular carcinoma model. (25th August 2021)

• Record Type: Journal Article
• Authors: Taïbi, Nadia; Al-balas, Qosay Ali; Bekari, Nadjia; Talhi, Oualid; Al Jabal, Ghazi Ahmad; Benali, Yasmine; Ameraoui, Rachid; Hadjadj, Mohamed; Taïbi, Amina; Boutaiba, Zahra Mouna; Abou-Mustapha, Mohamed; Khammar, Farida; Dergal, Fayçal; Hassaine, Ridha; Boukenna, Leila; Bachari, Khaldoun; Soares Silva, Artur Manuel
• Is Part Of: Chemico-biological interactions. Volume 345(2021)
• Publication Date: 2021-08-25
• Subjects: Molecular docking -- Coumarin-liposome -- Glyoxalase system -- GSH/NO -- Hepatocarcinoma -- Wistar rat; AGEs advance glycation end product -- Bcl2 B-cell lymphoma 2 -- CL cholesterol -- Coumarin-LP coumarin-liposome -- DB direct bilirubin -- DEN diethylnitrosamine -- DLS dynamic light scattering -- Glo-1 glyoxal-1 -- GSH glutathione reductase -- LDH lactate deshydrogenase -- MAPK mitogen activated proteins kinase -- MGO methylglyoxal -- MMP9 matrix metallopeptidase 9 -- NO nitric oxide -- OT-55: 3 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl]bis(4-hydroxycoumarin) -- PBS phosphate buffer solution -- PL phospholipids -- SEM Scanning Electron Microscope -- TB total bilirubin -- TEM Transmission Electron Microscopy -- WHO world health organization; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109511
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Methylglyoxal is a dicarbonyl compound recruited as a potential cytotoxic marker, initially presents in cells and considered as a metabolite of the glycolytic pathway. Our aim is to demonstrate the inhibitory effect of 3, 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl] Bis (4-hydroxycoumarin) on the glyoxalase system, and indirectly its anticancer activity. The docking of OT-55 was conducted by using Flexible docking protocol, ChiFlex and libdock tools inside the active site of Glo-I indicated that both hydrogen bonding and hydrophobic interactions contributed significantly in establishing potent binding with the active site which is selected as a strong inhibitor with high scoring values and maximum Gibbs free energy. Coumarin-liposome formulation was characterized and evaluated in vivo against chemically induced hepatocarcinoma in Wistar rats. After Diethylnitrosamine (DEN) induction, microscopic assessment was realized; precancerous lesions were developed showing an increase of both tumor-associated lymphocyte and multiple tumor acini supported by the blood investigation. Our finding also suggested a preferential uptake of liposomes respectively in liver, kidney, lung, brain and spleen in the DEN-treated animals. OT-55 has also been shown to inhibit the activity of Glo-I in vitro as well as in DEN-treated rats. An abnormal high level of MGO of up to 50% was recorded followed by a reduction in glucose consumption and lactate dehydrogenase production validated in the positive control. MGO generates apoptosis as depicted by focal hepatic lesions. Also, no deleterious effects in the control group were observed after testing our coumarin but rather a vascular reorganization leading to nodular regenerative hyperplasia. Involved in the detoxification process, liver GSH is restored in intoxicated rats, while no changes are seen between controls. At the endothelial cell, OT-55 appears to modulate the release of NO only in the DEN-treated group. OT-55 would behave both as an anticancer agent but also as an angiogenic factor regarding results obtained. Graphical abstract: Image 1 Highlights: 1. The docking of OT-55 inside the active site of Glo-I indicates a potent binding. OT-55 exhibits selective inhibitory effect on the glyoxalase system in vitro . OT-55 induces pro-apoptotic process in DEN-initiated hepatocarcinoma. In normal cells, it induces a vascular rearrangement. 5. A preferential distribution of the encapsulated coumarin in liver was noted. .