Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein

In this study, the interaction between clozapine, an atypical antipsychotic drug, and alpha-2-macroglobulin (?2M), a multipurpose anti-proteinase, was investigated under simulated (patho) physiological conditions using multiple spectroscopic techniques molecular modeling. It found that ?2M binds clozapine with moderate affinity (the binding constant of 0.9 × 105 M?1 at 37 °C). The preferable site for both clozapine's atropisomers revealed to be large pocket interface C D monomer subunits protein. Hydrogen bonds hydrophobic effect were proposed as dominant forces in complex formation. did not induce significant conformational change protein, confirmed by virtually unaltered secondary structure anti-proteinase activity. However, shielded each other from deleterious influence strong oxidants: sodium hypochlorite 2,2?-azobis-2-methyl-propanimidamide dihydrochloride (AAPH). Moreover, concentration range is usually targeted plasma during patients' treatment effectively protected activity AAPH-induced free radical overproduction. Our results suggest cooperation may path which these two molecules synergistically protect neural tissue against injury caused disturbed proteostasis or oxidative stress.