Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy
1 The normal and a mutant (S248F) human neuronal α4β2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower r...
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todo:paper_00071188_v136_n6_p883_Ortells2023-10-03T14:05:30Z Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy Ortells, M.O. Barrantes, G.E. Carbamazepine Epilepsy Molecular modelling Nicotinic receptor anticonvulsive agent carbamazepine functional group mutant protein nicotinic receptor serine anticonvulsive agent carbamazepine nicotinic receptor alpha4beta2 article autosomal dominant disorder binding affinity calcium transport dehydration drug binding site drug receptor binding frontal lobe epilepsy hydrogen bond molecular model molecular size physical chemistry prediction priority journal structure activity relation chemical structure chemistry dominant gene genetics human metabolism mutation Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Genes, Dominant Human Models, Molecular Mutation Receptors, Nicotinic Support, Non-U.S. Gov't Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Humans Receptors, Nicotinic 1 The normal and a mutant (S248F) human neuronal α4β2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower recovery from desensitization, a lower conductance, short open times, reduced calcium permeability, and is 3 fold more sensitive to CBZ, a drug used in the treatment of partial epilepsies. 2 Mutant channel properties are explained by the physicochemical properties of the two Phe248 side chains, including size and cation-π interaction, and their dynamic behaviour. A defective mechanism of dehydration might be responsible for the reduced calcium influx. 3 Phe248 residues are the main component of CBZ binding sites in the mutant, while this is not true for Ser248 in the normal receptor. 4 A higher number of blocking binding sites and a predicted higher affinity found for CBZ in the mutant account for its differential sensitivity to CBZ. 5 Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating Ki. 6 Normal vs mutant differences in Ki, enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7 For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug. Fil:Ortells, M.O. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00071188_v136_n6_p883_Ortells |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Carbamazepine Epilepsy Molecular modelling Nicotinic receptor anticonvulsive agent carbamazepine functional group mutant protein nicotinic receptor serine anticonvulsive agent carbamazepine nicotinic receptor alpha4beta2 article autosomal dominant disorder binding affinity calcium transport dehydration drug binding site drug receptor binding frontal lobe epilepsy hydrogen bond molecular model molecular size physical chemistry prediction priority journal structure activity relation chemical structure chemistry dominant gene genetics human metabolism mutation Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Genes, Dominant Human Models, Molecular Mutation Receptors, Nicotinic Support, Non-U.S. Gov't Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Humans Receptors, Nicotinic |
| spellingShingle |
Carbamazepine Epilepsy Molecular modelling Nicotinic receptor anticonvulsive agent carbamazepine functional group mutant protein nicotinic receptor serine anticonvulsive agent carbamazepine nicotinic receptor alpha4beta2 article autosomal dominant disorder binding affinity calcium transport dehydration drug binding site drug receptor binding frontal lobe epilepsy hydrogen bond molecular model molecular size physical chemistry prediction priority journal structure activity relation chemical structure chemistry dominant gene genetics human metabolism mutation Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Genes, Dominant Human Models, Molecular Mutation Receptors, Nicotinic Support, Non-U.S. Gov't Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Humans Receptors, Nicotinic Ortells, M.O. Barrantes, G.E. Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| topic_facet |
Carbamazepine Epilepsy Molecular modelling Nicotinic receptor anticonvulsive agent carbamazepine functional group mutant protein nicotinic receptor serine anticonvulsive agent carbamazepine nicotinic receptor alpha4beta2 article autosomal dominant disorder binding affinity calcium transport dehydration drug binding site drug receptor binding frontal lobe epilepsy hydrogen bond molecular model molecular size physical chemistry prediction priority journal structure activity relation chemical structure chemistry dominant gene genetics human metabolism mutation Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Genes, Dominant Human Models, Molecular Mutation Receptors, Nicotinic Support, Non-U.S. Gov't Anticonvulsants Carbamazepine Epilepsy, Frontal Lobe Humans Receptors, Nicotinic |
| description |
1 The normal and a mutant (S248F) human neuronal α4β2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower recovery from desensitization, a lower conductance, short open times, reduced calcium permeability, and is 3 fold more sensitive to CBZ, a drug used in the treatment of partial epilepsies. 2 Mutant channel properties are explained by the physicochemical properties of the two Phe248 side chains, including size and cation-π interaction, and their dynamic behaviour. A defective mechanism of dehydration might be responsible for the reduced calcium influx. 3 Phe248 residues are the main component of CBZ binding sites in the mutant, while this is not true for Ser248 in the normal receptor. 4 A higher number of blocking binding sites and a predicted higher affinity found for CBZ in the mutant account for its differential sensitivity to CBZ. 5 Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating Ki. 6 Normal vs mutant differences in Ki, enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7 For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug. |
| format |
JOUR |
| author |
Ortells, M.O. Barrantes, G.E. |
| author_facet |
Ortells, M.O. Barrantes, G.E. |
| author_sort |
Ortells, M.O. |
| title |
Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| title_short |
Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| title_full |
Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| title_fullStr |
Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| title_full_unstemmed |
Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| title_sort |
molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy |
| url |
http://hdl.handle.net/20.500.12110/paper_00071188_v136_n6_p883_Ortells |
| work_keys_str_mv |
AT ortellsmo molecularmodellingoftheinteractionsofcarbamazepineandanicotinicreceptorinvolvedintheautosomaldominantnocturnalfrontallobeepilepsy AT barrantesge molecularmodellingoftheinteractionsofcarbamazepineandanicotinicreceptorinvolvedintheautosomaldominantnocturnalfrontallobeepilepsy |
| _version_ |
1807318940621209600 |