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Realizing the recognition features of model antipsychotic compounds by important protein: Photochemical and computational studies

Paper ID Volume ID Publish Year Pages File Format Full-Text
29684 44431 2015 10 PDF Available
Title
Realizing the recognition features of model antipsychotic compounds by important protein: Photochemical and computational studies
Abstract

•The methyl group substituent on A- and C-rings has steric effects.•Phenothiazine drug is a potential effector.•Phenothiazine agent may affect the allosteric regulation.•Allosteric equilibrium of heme protein has probably changed.

Phenothiazine and its derivatives are the most effective antipsychotic drugs. They have been used in the treatment of serious mental and emotional symptoms including bipolar disorder, organic psychoses, psychotic depression and schizophrenia. However, these drugs cause serious side effects such as akathisia, hyperprolactinaemia and neuroleptic malignant syndrome. In this work we investigated the molecular recognition of two typical phenothiazine compounds, phenosafranin and safranin O by the most pivotal heme protein hemoglobin using steady state and time-resolved fluorescence, extrinsic 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescent probe, circular dichroism (CD) along with computational modeling. Results show phenothiazines complex with protein via formation of adducts at 298 K with moderate strengths of 3.555 × 104 M−1 and 2.567 × 104 M−1 for the hemoglobin–phenosafranin and hemoglobin–safranin O, respectively. We also found phenothiazines were effectors at the protein allosteric site, which affects the allosteric equilibrium. Further, time-resolved fluorescence and hydrophobic ANS experiments showed the static mechanism is dominated for the shrinkage in the fluorescence intensity of β-37 Trp residue at the α1β2 interface. The stoichiometric proportion of the protein–drug adduct is 1:1, as derived from Job’s plot. Several crucial noncovalent bonds, including hydrogen bonds, π–π stacking and hydrophobic interactions played a major role in stabilizing the noncovalent conjugates. Based on three-dimensional fluorescence, we concluded that the conformation of hemoglobin is partially destabilized after recognition with phenothiazines. These alterations were confirmed by far-UV CD spectra that showed the α-helix of protein decreased from 78.3% in free hemoglobin to 62.8% and 64.8% in hemoglobin–phenosafranin and hemoglobin–safranin O, respectively. Computer-aided molecular docking was consistent, indicating that both phenothiazines are situated within the pocket composed of α1 and β2 subunits. Affinity of hemoglobin to phenosafranin is superior compared with safranin O. This difference may be explained by the methyl group substituent on A- and C-rings, and by the different molecular volume between phenosafranin and safranin O. Our data provides further explanation of the overall pharmacokinetics of phenothiazines and sheds light on the allosteric regulation of heme proteins.

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Keywords
Ala, alanine; ANS, 8-anilino-1-naphthalenesulfonic acid; Asn, asparagine; CD, circular dichroism; IRF, instrument response function; Leu, leucine; Lys, lysine; Phe, phenylalanine; R, correlation coefficient; S.D., standard deviation; Tris, tris(hydroxymet
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Realizing the recognition features of model antipsychotic compounds by important protein: Photochemical and computational studies
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Photochemistry and Photobiology B: Biology - Volume 148, July 2015, Pages 21–30
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us