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

Korkmaz I. N., Güller U., Kalın R., ÖZDEMİR H., KÜFREVİOĞLU Ö. İ.

Chemistry and Biodiversity, cilt.20, sa.5, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 20 Sayı: 5
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1002/cbdv.202201220
  • Dergi Adı: Chemistry and Biodiversity
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Aquatic Science & Fisheries Abstracts (ASFA), CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: benzoates, glutathione S-transferases, glutathione reductase, toxicity estimation, molecular docking, INDUCED OXIDATIVE STRESS, S-TRANSFERASE, PLACENTAL FORM, PURIFICATION, MECHANISMS, REDUCTASE, REDOX, INHIBITION, CARCINOMA, PRODRUG
  • Atatürk Üniversitesi Adresli: Evet

Özet

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.