Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin
| Autor: | Norbert Roewer, Jens-Albert Broscheit, Tamás Sohajda, Carola Förster, Istaván Puskas, Sergey Shityakov |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Molecular model Cell Survival Pharmaceutical Science torsional energy Medicinal chemistry Article Analytical Chemistry lcsh:QD241-441 Mice symbols.namesake lcsh:Organic chemistry Computational chemistry Ionization Drug Discovery Animals Humans Molecule trimethyl-β-cyclodextrin Physical and Theoretical Chemistry Cells Cultured free energy of solvation chemistry.chemical_classification ddc:615 Ligand efficiency Cyclodextrin Chemistry beta-Cyclodextrins Organic Chemistry quantum mechanics Solvation Water molecular docking transition state Binding constant Gibbs free energy midazolam Gibbs free energy of binding Chemistry (miscellaneous) symbols Thermodynamics Molecular Medicine Endothelium Vascular |
| Zdroj: | Molecules, Vol 19, Iss 10, Pp 16861-16876 (2014) Molecules Volume 19 Issue 10 Pages 16861-16876 |
| Popis: | We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy ((Delta G_{solv}^{CR}) = −9.98 kcal·mol(^{−1})), which has a minimal (Delta G_{solv}^{OR}) of −67.01 kcal·mol(^{−1}). A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding ((Delta G_{bind})) value of −5.57 ± 0.02 kcal·mol(^{−1}), an equilibrium binding constant ((K_{b})) of 79.89 ± 2.706 μM, and a ligand efficiency index ((LE_{lig})) of −0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations. |
| Databáze: | OpenAIRE |
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