Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin
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...
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MDPI AG
2014-10-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/19/10/16861 |
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| author | Sergey Shityakov Tamás Sohajda István Puskás Norbert Roewer Carola Förster Jens-Albert Broscheit |
| author_facet | Sergey Shityakov Tamás Sohajda István Puskás Norbert Roewer Carola Förster Jens-Albert Broscheit |
| author_sort | Sergey Shityakov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T13:18:33Z |
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| id | doaj.art-c6fc04b86bc8418a8feb44b477f57c34 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-21T13:18:33Z |
| publishDate | 2014-10-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c6fc04b86bc8418a8feb44b477f57c342022-12-21T19:02:40ZengMDPI AGMolecules1420-30492014-10-011910168611687610.3390/molecules191016861molecules191016861Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-CyclodextrinSergey Shityakov0Tamás Sohajda1István Puskás2Norbert Roewer3Carola Förster4Jens-Albert Broscheit5Department of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, GermanyCycloLab Cyclodextrin Research & Development Laboratory Ltd., H-1097 Budapest, HungaryCycloLab Cyclodextrin Research & Development Laboratory Ltd., H-1097 Budapest, HungaryDepartment of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, GermanyDepartment of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, GermanyDepartment of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, GermanyWe 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.http://www.mdpi.com/1420-3049/19/10/16861trimethyl-β-cyclodextrinmidazolamtransition statemolecular dockingGibbs free energy of bindingquantum mechanicsfree energy of solvationtorsional energy |
| spellingShingle | Sergey Shityakov Tamás Sohajda István Puskás Norbert Roewer Carola Förster Jens-Albert Broscheit Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin Molecules trimethyl-β-cyclodextrin midazolam transition state molecular docking Gibbs free energy of binding quantum mechanics free energy of solvation torsional energy |
| title | Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin |
| title_full | Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin |
| title_fullStr | Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin |
| title_full_unstemmed | Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin |
| title_short | Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin |
| title_sort | ionization states cellular toxicity and molecular modeling studies of midazolam complexed with trimethyl β cyclodextrin |
| topic | trimethyl-β-cyclodextrin midazolam transition state molecular docking Gibbs free energy of binding quantum mechanics free energy of solvation torsional energy |
| url | http://www.mdpi.com/1420-3049/19/10/16861 |
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