The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands
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{"title"=>"The quantum nature of drug-receptor interactions: Deuteration changes binding affinities for histamine receptor ligands", "type"=>"journal", "authors"=>[{"first_name"=>"Mojca", "last_name"=>"Kržan", "scopus_author_id"=>"6602090689"}, {"first_name"=>"Robert", "last_name"=>"Vianello", "scopus_author_id"=>"6602140934"}, {"first_name"=>"Aleksandra", "last_name"=>"Maršavelski", "scopus_author_id"=>"55932526700"}, {"first_name"=>"Matej", "last_name"=>"Repič", "scopus_author_id"=>"53985217300"}, {"first_name"=>"Maja", "last_name"=>"Zakšek", "scopus_author_id"=>"57189367323"}, {"first_name"=>"Kristina", "last_name"=>"Kotnik", "scopus_author_id"=>"57194480867"}, {"first_name"=>"Estera", "last_name"=>"Fijan", "scopus_author_id"=>"57189359849"}, {"first_name"=>"Janez", "last_name"=>"Mavri", "scopus_author_id"=>"55961940900"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84969760749", "pui"=>"610342646", "doi"=>"10.1371/journal.pone.0154002", "sgr"=>"84969760749", "pmid"=>"27159606"}, "id"=>"6644dde5-0b86-3595-a5d6-a8dd5b701de9", "abstract"=>"© 2016 Kržan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N-H and O-H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure.", "link"=>"http://www.mendeley.com/research/quantum-nature-drugreceptor-interactions-deuteration-changes-binding-affinities-histamine-receptor-l", "reader_count"=>15, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Master"=>5, "Other"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Master"=>5, "Other"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>1, "Materials Science"=>1, "Medicine and Dentistry"=>2, "Agricultural and Biological Sciences"=>1, "Neuroscience"=>1, "Physics and Astronomy"=>1, "Chemistry"=>4, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>4}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/5210089"], "description"=>"<div><p>In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to <sup>3</sup>H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154002#pone.0154002.s001\" target=\"_blank\">S1 Table</a>) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. <i>Ab initio</i> quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains <i>in silico</i> discrimination between agonists and antagonists based on the receptor structure.</p></div>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368068, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002", "stats"=>{"downloads"=>1, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_Quantum_Nature_of_Drug-Receptor_Interactions_Deuteration_Changes_Binding_Affinities_for_Histamine_Receptor_Ligands/3368068", "title"=>"The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands", "pos_in_sequence"=>1, "defined_type"=>3, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210191"], "description"=>"<p>The choice of the dielectric constant in the computations is indicated in round brackets.</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368134, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Computational_scheme_of_histamine_monocation_interacting_with_five_water_molecules_to_calculate_the_free_energy_of_hydration_/3368134", "title"=>"Computational scheme of histamine monocation interacting with five water molecules to calculate the free energy of hydration.", "pos_in_sequence"=>6, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210152"], "description"=>"<p>Deuteration significantly (p < 0.0001) decreased the pIC<sub>50</sub> of 2-methylhistamine (8.38 ± 0.13 (control) to 6.85 ± 0.16 (D<sub>2</sub>O)), whereas it significantly (p < 0.05) increased the pIC<sub>50</sub> of histamine (7.25 ± 0.11 (control) to 7.80 ± 0.16 (D<sub>2</sub>O)) and marginally increased the pIC<sub>50</sub> value of 4-methylhistamine from 7.31 ± 0.28 (control) to 7.67 ± 0.13 (D<sub>2</sub>O).</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368107, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Inhibition_of_specific_binding_of_sup_3_sup_H-_tiotidine_in_cultured_astrocytes_with_histamine_2-_and_4-methylhistamine_2-MeHi_and_4-MeHi_respectively_/3368107", "title"=>"Inhibition of specific binding of <sup>3</sup>H- tiotidine in cultured astrocytes with histamine, 2- and 4-methylhistamine; 2-MeHi and 4-MeHi, respectively.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210224"], "description"=>"<p>All the structures were obtained on the M06–2X/6–31+G(d,p) level with CPCM solvent reaction field. Please note that beside dielectric constant of 4, a value of 20 was also considered.</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368146, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Computational_scheme_to_calculate_the_interaction_energy_between_the_histamine_monocation_and_the_receptor_site_/3368146", "title"=>"Computational scheme to calculate the interaction energy between the histamine monocation and the receptor site.", "pos_in_sequence"=>7, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210110"], "description"=>"<p>Astrocytes were incubated for 15 minutes with the indicated concentrations of <sup>3</sup>H-tiotidine in regular phosphate buffer (A) or in phosphate buffer made in D<sub>2</sub>O (B). Results are presented as a mean value ± SEM of two experiments carried out in triplicate (n = 6).</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368083, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Binding_of_sup_3_sup_H-tiotidine_to_cultured_neonatal_rat_astrocytes_/3368083", "title"=>"Binding of <sup>3</sup>H-tiotidine to cultured neonatal rat astrocytes.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210170"], "description"=>"<p>The incept shows the structure of the receptor model employed in quantum-chemical analysis, where the selected amino acid residues were truncated at the corresponding α–carbon atoms which positions were kept frozen during geometry optimization.</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368119, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_structure_of_the_H2_homology_model_with_bound_histamine_/3368119", "title"=>"The structure of the H2 homology model with bound histamine.", "pos_in_sequence"=>5, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210242"], "description"=>"<p>Changes in the energy of histamine hydration (ΔE<sub>HYDR</sub>), H2 receptor interaction (ΔE<sub>INTER</sub>) and total receptor binding (ΔE<sub>BIND</sub>) upon deuteration.</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368158, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Changes_in_the_energy_of_histamine_hydration_E_sub_HYDR_sub_H2_receptor_interaction_E_sub_INTER_sub_and_total_receptor_binding_E_sub_BIND_sub_upon_deuteration_/3368158", "title"=>"Changes in the energy of histamine hydration (ΔE<sub>HYDR</sub>), H2 receptor interaction (ΔE<sub>INTER</sub>) and total receptor binding (ΔE<sub>BIND</sub>) upon deuteration.", "pos_in_sequence"=>8, "defined_type"=>3, "published_date"=>"2016-05-09 05:58:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/5210128"], "description"=>"<p><sup>3</sup>H-tiotidine binds to a single population of binding sites with a K<sub>D</sub> of = 4.7 ± 1.0 nM and B<sub>max</sub> of 18.6 ± 1.7 fmol/mg protein. The deuterated medium does not significantly change the binding parameters of <sup>3</sup>H-tiotidine to astrocytic H2 receptor binding sites—K<sub>D</sub> changed to 7.4 ± 2.4 nM and B<sub>max</sub> dropped to 17.1 ± 2.7 fmol/mg protein.</p>", "links"=>[], "tags"=>["Deuteration Changes Binding Affinities", "homology H 2 model", "deuteration", "understanding receptor activation", "ligand receptor binding", "H 2 receptor", "histamine", "rat astrocytes", "S 1 Table", "H 2 receptor binding sites", "Histamine Receptor Ligands", "receptor binding site", "displacing radiolabeled tiotidine", "Tyr 250 residue"], "article_id"=>3368095, "categories"=>["Biophysics", "Biochemistry", "Molecular Biology", "Pharmacology", "Chemical Sciences not elsewhere classified", "Immunology", "Biological Sciences not elsewhere classified"], "users"=>["Mojca Kržan", "Robert Vianello", "Aleksandra Maršavelski", "Matej Repič", "Maja Zakšek", "Kristina Kotnik", "Estera Fijan", "Janez Mavri"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0154002.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Specific_sup_3_sup_H-tiotidine_binding_to_cultured_neonatal_rat_astrocytes_/3368095", "title"=>"Specific <sup>3</sup>H-tiotidine binding to cultured neonatal rat astrocytes.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-05-09 05:58:22"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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Net::HTTPTooManyRequests

Source
Scopus
Time
2019-08-27 19:05:26 UTC
Target URL
https://api.elsevier.com/content/search/index:SCOPUS?query=DOI(10.1371%2Fjournal.pone.0154002)
Trace

/app/models/concerns/networkable.rb:21:in `get_result'
/app/models/source.rb:165:in `get_data'
/app/models/retrieval_status.rb:47:in `perform_get_data'
/app/jobs/source_job.rb:52:in `block (2 levels) in perform'
/app/jobs/source_job.rb:51:in `block in perform'
/app/jobs/source_job.rb:35:in `each'
/app/jobs/source_job.rb:35:in `perform'