Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein
Samo za registrovane korisnike
2021
Autori
Šunderić, MilošVasović, Tamara
Milčić, Miloš K.
Miljević, Čedo
Nedić, Olgica
Nikolić, Milan
Gligorijević, Nikola
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
In this study, the interaction between clozapine, an atypical antipsychotic drug, and alpha-2-macroglobulin (α2M), a multipurpose anti-proteinase, was investigated under simulated (patho) physiological conditions using multiple spectroscopic techniques and molecular modeling. It was found that α2M binds clozapine with a moderate affinity (the binding constant of 0.9 × 105 M−1 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 α2M secondary structure and anti-proteinase activity. However, both clozapine and α2M shielded each other from the deleterious influence of strong oxidants: sodium hypochlorite and 2,2′-azobis-2-methyl-propanimidamide dihydrochlor...ide (AAPH). Moreover, clozapine in a concentration range that is usually targeted in the plasma during patients' treatment effectively protected the anti-proteinase activity of α2M under AAPH-induced free radical overproduction. Our results suggest that the cooperation between α2M and clozapine may be a path by which these two molecules synergistically protect neural tissue against injury caused by disturbed proteostasis or oxidative stress.
Ključne reči:
Alpha-2-macroglobulin / Clozapine / Protein-ligand interactionIzvor:
International Journal of Biological Macromolecules, 2021, 183, 502-512Izdavač:
- Elsevier
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200019 (Univerzitet u Beogradu, Institut za primenu nuklearne energije - INEP) (RS-MESTD-inst-2020-200019)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200168 (Univerzitet u Beogradu, Hemijski fakultet) (RS-MESTD-inst-2020-200168)
Napomena:
- Supplementary material: https://cherry.chem.bg.ac.rs/handle/123456789/4541
Povezane informacije:
DOI: 10.1016/j.ijbiomac.2021.04.155
ISSN: 0141-8130
WoS: 000671549000002
Scopus: 2-s2.0-85105114630
URI
https://www.sciencedirect.com/science/article/pii/S0141813021009284https://cherry.chem.bg.ac.rs/handle/123456789/4538
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Šunderić, Miloš AU - Vasović, Tamara AU - Milčić, Miloš K. AU - Miljević, Čedo AU - Nedić, Olgica AU - Nikolić, Milan AU - Gligorijević, Nikola PY - 2021 UR - https://www.sciencedirect.com/science/article/pii/S0141813021009284 UR - https://cherry.chem.bg.ac.rs/handle/123456789/4538 AB - In this study, the interaction between clozapine, an atypical antipsychotic drug, and alpha-2-macroglobulin (α2M), a multipurpose anti-proteinase, was investigated under simulated (patho) physiological conditions using multiple spectroscopic techniques and molecular modeling. It was found that α2M binds clozapine with a moderate affinity (the binding constant of 0.9 × 105 M−1 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 α2M secondary structure and anti-proteinase activity. However, both clozapine and α2M 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 α2M under AAPH-induced free radical overproduction. Our results suggest that the cooperation between α2M and clozapine may be a path by which these two molecules synergistically protect neural tissue against injury caused by disturbed proteostasis or oxidative stress. PB - Elsevier T2 - International Journal of Biological Macromolecules T1 - Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein VL - 183 SP - 502 EP - 512 DO - 10.1016/j.ijbiomac.2021.04.155 ER -
@article{ author = "Šunderić, Miloš and Vasović, Tamara and Milčić, Miloš K. and Miljević, Čedo and Nedić, Olgica and Nikolić, Milan and Gligorijević, Nikola", year = "2021", abstract = "In this study, the interaction between clozapine, an atypical antipsychotic drug, and alpha-2-macroglobulin (α2M), a multipurpose anti-proteinase, was investigated under simulated (patho) physiological conditions using multiple spectroscopic techniques and molecular modeling. It was found that α2M binds clozapine with a moderate affinity (the binding constant of 0.9 × 105 M−1 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 α2M secondary structure and anti-proteinase activity. However, both clozapine and α2M 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 α2M under AAPH-induced free radical overproduction. Our results suggest that the cooperation between α2M and clozapine may be a path by which these two molecules synergistically protect neural tissue against injury caused by disturbed proteostasis or oxidative stress.", publisher = "Elsevier", journal = "International Journal of Biological Macromolecules", title = "Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein", volume = "183", pages = "502-512", doi = "10.1016/j.ijbiomac.2021.04.155" }
Šunderić, M., Vasović, T., Milčić, M. K., Miljević, Č., Nedić, O., Nikolić, M.,& Gligorijević, N.. (2021). Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein. in International Journal of Biological Macromolecules Elsevier., 183, 502-512. https://doi.org/10.1016/j.ijbiomac.2021.04.155
Šunderić M, Vasović T, Milčić MK, Miljević Č, Nedić O, Nikolić M, Gligorijević N. Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein. in International Journal of Biological Macromolecules. 2021;183:502-512. doi:10.1016/j.ijbiomac.2021.04.155 .
Šunderić, Miloš, Vasović, Tamara, Milčić, Miloš K., Miljević, Čedo, Nedić, Olgica, Nikolić, Milan, Gligorijević, Nikola, "Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein" in International Journal of Biological Macromolecules, 183 (2021):502-512, https://doi.org/10.1016/j.ijbiomac.2021.04.155 . .