Inhibition of cholinesterases by safranin O: Integration of inhibition kinetics with molecular docking simulations

ÖNDER S., SARI S., TACAL Ö.

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, cilt.698, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 698
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.abb.2020.108728
  • Dergi Adı: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Safranin O, Cholinesterase inhibition, Acetylcholinesterase, Butyrylcholinesterase, Molecular docking, TOLUIDINE BLUE O, ALZHEIMERS-DISEASE, CATIONIC TRIARYLMETHANE, PSEUDOMONAS-AERUGINOSA, CRYSTAL-STRUCTURE, ACETYLCHOLINESTERASE, BUTYRYLCHOLINESTERASE, BINDING, PROTEIN, MECHANISMS
  • Hacettepe Üniversitesi Adresli: Evet

Özet

In the present study, the inhibitory mechanisms and effects of a synthetic phenazine dye, safranin O (SO) on human plasma butyrylcholinesterase (BChE), human erythrocyte acetylcholinesterase (AChE) and recombinant BChE mutants were investigated. Kinetic studies showed the following information: SO leaded to linear competitive inhibition of human plasma BChE with K-i = 0.44 +/- 0.085 mu M; alpha = infinity. It acted as a hyperbolic noncompetitive inhibitor of human erythrocyte AChE with K-i = 0.69 +/- 0.13; alpha = 1;beta = 0.08 +/- 0.02. On the other hand, the inhibitory effects of SO on two BChE mutants, where A328 was modified to either F or Y, revealed differences in terms of inhibitory patterns and K-i values, compared to the obtained results with recombinant wild type BChE. SO was found to act as a linear competitive inhibitor of A328F and A328Y BChE mutants. Compared to recombinant wild type BChE, A328Y and A328F BChE mutants caused a 4 and 10-fold decrease in K-i value for SO, respectively. These findings were supported by molecular modelling studies. In conclusion, SO is a potent inhibitor of human cholinesterases and may be useful in the design and development of new drugs for the treatment of AD.