Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane
Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass that is widely used in pharmacology and that can be incorporated in membranes. We studied its interaction with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid...
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MDPI AG
2021-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/9/1304 |
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| author | Alessio Ausili Illya Yakymenko José A. Teruel Juan C. Gómez-Fernández |
| author_facet | Alessio Ausili Illya Yakymenko José A. Teruel Juan C. Gómez-Fernández |
| author_sort | Alessio Ausili |
| collection | DOAJ |
| description | Clotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass that is widely used in pharmacology and that can be incorporated in membranes. We studied its interaction with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid vesicles by using differential scanning calorimetry and found that the transition temperature decreases progressively as the concentration of clotrimazole increases. However, the temperature of completion of the transition remained constant despite the increase of clotrimazole concentration, suggesting the formation of fluid immiscibility. <sup>1</sup>H-NMR and <sup>1</sup>H NOESY MAS-NMR were employed to investigate the location of clotrimazole in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid membranes. In the presence of clotrimazole, all the resonances originating from POPC were shifted upfield, but mainly those corresponding to C2 and C3 of the fatty acyl, chains suggesting that clotrimazole aromatic rings preferentially locate near these carbons. In the same way, 2D-NOESY measurements showed that the highest cross-relaxation rates between protons of clotrimazole and POPC were with those bound to the C2 and C3 carbons of the fatty acyl chains. Molecular dynamics simulations indicated that clotrimazole is located near the top of the hydrocarbon-chain phase, with the nitrogen atoms of the imidazole ring of clotrimazole being closest to the polar group of the carbonyl moiety. These results are in close agreement with the NMR and the conclusion is that clotrimazole is located near the water–lipid interface and in the upper part of the hydrophobic bilayer. |
| first_indexed | 2024-03-10T07:52:21Z |
| format | Article |
| id | doaj.art-81c5350a94c24e03b1727aa7c54d383d |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T07:52:21Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-81c5350a94c24e03b1727aa7c54d383d2023-11-22T12:10:39ZengMDPI AGBiomolecules2218-273X2021-09-01119130410.3390/biom11091304Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the MembraneAlessio Ausili0Illya Yakymenko1José A. Teruel2Juan C. Gómez-Fernández3Department of Biochemistry and Molecular Biology (A), Faculty of Veterinary Science, International Campus of Excellence Mare Nostrum, Universidad de Murcia, Apartado. 4021, E-30100 Murcia, SpainDepartment of Biochemistry and Molecular Biology (A), Faculty of Veterinary Science, International Campus of Excellence Mare Nostrum, Universidad de Murcia, Apartado. 4021, E-30100 Murcia, SpainDepartment of Biochemistry and Molecular Biology (A), Faculty of Veterinary Science, International Campus of Excellence Mare Nostrum, Universidad de Murcia, Apartado. 4021, E-30100 Murcia, SpainDepartment of Biochemistry and Molecular Biology (A), Faculty of Veterinary Science, International Campus of Excellence Mare Nostrum, Universidad de Murcia, Apartado. 4021, E-30100 Murcia, SpainClotrimazole (1-[(2-chlorophenyl)-diphenylmethyl]-imidazole) is an azole antifungal drug belonging to the imidazole subclass that is widely used in pharmacology and that can be incorporated in membranes. We studied its interaction with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid vesicles by using differential scanning calorimetry and found that the transition temperature decreases progressively as the concentration of clotrimazole increases. However, the temperature of completion of the transition remained constant despite the increase of clotrimazole concentration, suggesting the formation of fluid immiscibility. <sup>1</sup>H-NMR and <sup>1</sup>H NOESY MAS-NMR were employed to investigate the location of clotrimazole in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid membranes. In the presence of clotrimazole, all the resonances originating from POPC were shifted upfield, but mainly those corresponding to C2 and C3 of the fatty acyl, chains suggesting that clotrimazole aromatic rings preferentially locate near these carbons. In the same way, 2D-NOESY measurements showed that the highest cross-relaxation rates between protons of clotrimazole and POPC were with those bound to the C2 and C3 carbons of the fatty acyl chains. Molecular dynamics simulations indicated that clotrimazole is located near the top of the hydrocarbon-chain phase, with the nitrogen atoms of the imidazole ring of clotrimazole being closest to the polar group of the carbonyl moiety. These results are in close agreement with the NMR and the conclusion is that clotrimazole is located near the water–lipid interface and in the upper part of the hydrophobic bilayer.https://www.mdpi.com/2218-273X/11/9/1304clotrimazolemodel membranelocationmembrane fluidity |
| spellingShingle | Alessio Ausili Illya Yakymenko José A. Teruel Juan C. Gómez-Fernández Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane Biomolecules clotrimazole model membrane location membrane fluidity |
| title | Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane |
| title_full | Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane |
| title_fullStr | Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane |
| title_full_unstemmed | Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane |
| title_short | Clotrimazole Fluidizes Phospholipid Membranes and Localizes at the Hydrophobic Part near the Polar Part of the Membrane |
| title_sort | clotrimazole fluidizes phospholipid membranes and localizes at the hydrophobic part near the polar part of the membrane |
| topic | clotrimazole model membrane location membrane fluidity |
| url | https://www.mdpi.com/2218-273X/11/9/1304 |
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