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Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein.
- Source :
-
International journal of biological macromolecules [Int J Biol Macromol] 2021 Jul 31; Vol. 183, pp. 502-512. Date of Electronic Publication: 2021 Apr 28. - Publication Year :
- 2021
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Abstract
- In this study, the interaction between clozapine, an atypical antipsychotic drug, and alpha-2-macroglobulin (α <subscript>2</subscript> M), a multipurpose anti-proteinase, was investigated under simulated (patho) physiological conditions using multiple spectroscopic techniques and molecular modeling. It was found that α <subscript>2</subscript> M binds clozapine with a moderate affinity (the binding constant of 0.9 × 10 <superscript>5</superscript> M <superscript>-1</superscript> at 37 °C). The preferable binding site for both clozapine's atropisomers was revealed to be a large pocket at the interface of C and D monomer subunits of the protein. Hydrogen bonds and the hydrophobic effect were proposed as dominant forces in complex formation. The binding of clozapine did not induce significant conformational change of the protein, as confirmed by virtually unaltered α <subscript>2</subscript> M secondary structure and anti-proteinase activity. However, both clozapine and α <subscript>2</subscript> M shielded each other from the deleterious influence of strong oxidants: sodium hypochlorite and 2,2'-azobis-2-methyl-propanimidamide dihydrochloride (AAPH). Moreover, clozapine in a concentration range that is usually targeted in the plasma during patients' treatment effectively protected the anti-proteinase activity of α <subscript>2</subscript> M under AAPH-induced free radical overproduction. Our results suggest that the cooperation between α <subscript>2</subscript> M and clozapine may be a path by which these two molecules synergistically protect neural tissue against injury caused by disturbed proteostasis or oxidative stress.<br /> (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Subjects :
- Antipsychotic Agents chemistry
Binding Sites
Clozapine chemistry
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Molecular Docking Simulation
Oxidation-Reduction
Protein Binding
Protein Conformation
Structure-Activity Relationship
alpha-Macroglobulins chemistry
Antipsychotic Agents metabolism
Clozapine metabolism
Oxidative Stress
alpha-Macroglobulins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0003
- Volume :
- 183
- Database :
- MEDLINE
- Journal :
- International journal of biological macromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 33930446
- Full Text :
- https://doi.org/10.1016/j.ijbiomac.2021.04.155