TY  - JOUR
A1  - Shityakov, Sergey
A1  - Puskás, István
A1  - Pápai, Katalin
A1  - Salvador, Ellaine
A1  - Roewer, Norbert
A1  - Förster, Carola
A1  - Broscheit, Jens-Albert
T1  - Sevoflurane-sulfobutylether-\(\beta\)-cyclodextrin complex: preparation, characterization, cellular toxicity, molecular modeling and blood-brain barrier transport studies
JF  - Molecules
N2  - The objective of the present investigation was to study the ability of sulfobutylether-\(\beta\)-cyclodextrin (SBECD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBE\(\beta\)CD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (P\(_{app}\)). In addition, SEV binding affinity to SBE\(\beta\)CD was confirmed by a minimal Gibbs free energy of binding (ΔG\(_{bind}\)) value of -1.727 ± 0.042 kcal・mol\(^{-1}\) and an average binding constant (K\(_{b}\)) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.
KW  - pharmaceutical applications
KW  - in vitro
KW  - propranolol
KW  - water
KW  - primary microvascular endothelial cells
KW  - molecular liphophilicity potential
KW  - molecular docking
KW  - blood-brain barrier
KW  - ulfobutylether-\(\beta\)-cyclodextrin
KW  - sevoflurane
KW  - cyclodextrin formulations
KW  - safety
KW  - etomidate
KW  - formulations
KW  - hydrochloride
KW  - ether
KW  - intestinal absorption
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148543
VL  - 20
ER  - 
TY  - JOUR
A1  - Shityakov, Sergey
A1  - Puskás, István
A1  - Roewer, Norbert
A1  - Förster, Carola
A1  - Broscheit, Jens
T1  - Three-dimensional quantitative structure-activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors
JF  - Advances and Applications in Bioinformatics and Chemistry
N2  - The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure-activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q (2) of 0.795 (0.687) and r (2) of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r (2) of 0.821 (CoMFA) and r (2) of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) values were confirmed by molecular docking into the CYP3A4 active site with r (2) of 0.66. The results obtained from this study are useful for a better understanding of the effects of anthocyanin derivatives on inhibition of carcinogen activation and cellular DNA damage.
KW  - molecular docking
KW  - three-dimensional quantitative structure–activity relationship
KW  - cytochrome P450 3A4
KW  - comparative molecular similarity index analysis
KW  - comparative molecular field analysis
KW  - carcinogen activation
KW  - anthocyanin derivatives
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120226
VL  - 7
ER  -