Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?

• Published in: International journal of molecular sciences Vol. 24; no. 10; p. 8921
• Main Authors: Platanić Arizanović, Lena, Gligorijević, Nikola, Cvijetić, Ilija, Mijatović, Aleksandar, Ristivojević, Maja Krstić, Minić, Simeon, Kokić, Aleksandra Nikolić, Miljević, Čedo, Nikolić, Milan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.05.2023; MDPI
• Subjects: Antipsychotic Agents - pharmacology; Antipsychotic drugs; Antipsychotics; Benzodiazepines; binding; Binding sites; Clozapine; Clozapine - pharmacology; Drug delivery systems; Drug interaction; Drugs; Erythrocytes; Free radicals; Glycosylated hemoglobin; Heme; Hemoglobin; human hemoglobin; Humans; Hydrophobicity; Ligands; Lipophilic; Melting points; Molecular docking; Molecular Docking Simulation; Olanzapine; Oxidation; Pharmacodynamics; Pharmacokinetics; Physiological aspects; Protein transport; Proteins; Psychosis; Psychotropic drugs; Schizophrenia; sertindole; Temperature; Ziprasidone; Serbia; human hemoglobin; antipsychotics; binding; clozapine; ziprasidone; sertindole; interactions
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24108921

Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van't Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~10 M ), the highest observed for clozapine (2.2 × 10 M at 25 °C). The clozapine binding showed "friendly" effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible "foe". Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.