Structure‐Activity Relationship of Methyl 4‐Aminobenzoate Derivatives as Being Drug Candidate Targeting Glutathione Related Enzymes: in Vitro and in Silico Approaches

Abstract

A thiol compound, glutathione, is essential for healthy cell defence against xenobiotics and oxidative stress. Glutathione reductase (GR) and glutathione S‐transferase (GST) are two glutathione‐related enzymes that function in the antioxidant and the detoxification systems. In this study, potential inhibitory effects of methyl 4‐aminobenzoate derivatives on GR and GST were examined in vitro. GR and GST were isolated from human erythrocytes with 7.63 EU/mg protein and 5.66 EU/mg protein specific activity, respectively. It was found that compound 1 (methyl 4‐amino‐3‐bromo‐5‐fluorobenzoate with Ki value of 0.325±0.012 μM) and compound 5 (methyl 4‐amino‐2‐nitrobenzoate with Ki value of 92.41±22.26 μM) inhibited GR and GST stronger than other derivatives. Furthermore, a computer‐aided method was used to predict the binding affinities of derivatives, ADME characteristics, and toxicities. Derivatives 4 (methyl 4‐amino‐2‐bromobenzoate) and 6 (methyl 4‐amino‐2‐chlorobenzoate) were estimated to have the lowest binding energies into GR and GST receptors, respectively according to results of in silico studies.

Investigation of the Effects of 1,2,4‐Triazole and Thiazole Ring‐Containing Hybrid Molecules on Carbonic Anhydrase I and II

“…To predict possible types of interactions between inhibitors and enzymes, molecular docking analyses were realized using AutoDock 4.2 software. First, ligands (1,2,4-Triazole and Thiazole Ring-Containing Hybrid Molecules) were drawn by ChemDraw software, and their optimization and energy minimization were carried out using Avogadro software as described in Korkmaz et al (2023). [36][37][38] Ligands were made ready for docking as *pdbqt files by utilizing AutoDock 4.2.…”

“…First, ligands (1,2,4-Triazole and Thiazole Ring-Containing Hybrid Molecules) were drawn by ChemDraw software, and their optimization and energy minimization were carried out using Avogadro software as described in Korkmaz et al (2023). [36][37][38] Ligands were made ready for docking as *pdbqt files by utilizing AutoDock 4.2. [39] Secondly, the PDB structures of hCA I (3lxe) [40] and hCA II (5aml) receptors [41] were retrieved from the protein data bank (http://www.…”