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The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands.
PLoS One. 2016; 11(5):e0154002.Plos

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia.Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia.Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Ljubljana, Slovenia.Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Ljubljana, Slovenia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27159606

Citation

Kržan, Mojca, et al. "The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands." PloS One, vol. 11, no. 5, 2016, pp. e0154002.
Kržan M, Vianello R, Maršavelski A, et al. The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands. PLoS ONE. 2016;11(5):e0154002.
Kržan, M., Vianello, R., Maršavelski, A., Repič, M., Zakšek, M., Kotnik, K., Fijan, E., & Mavri, J. (2016). The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands. PloS One, 11(5), e0154002. https://doi.org/10.1371/journal.pone.0154002
Kržan M, et al. The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands. PLoS ONE. 2016;11(5):e0154002. PubMed PMID: 27159606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands. AU - Kržan,Mojca, AU - Vianello,Robert, AU - Maršavelski,Aleksandra, AU - Repič,Matej, AU - Zakšek,Maja, AU - Kotnik,Kristina, AU - Fijan,Estera, AU - Mavri,Janez, Y1 - 2016/05/09/ PY - 2015/12/03/received PY - 2016/03/21/accepted PY - 2016/5/10/entrez PY - 2016/5/10/pubmed PY - 2017/7/18/medline SP - e0154002 EP - e0154002 JF - PloS one JO - PLoS ONE VL - 11 IS - 5 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/27159606/The_Quantum_Nature_of_Drug_Receptor_Interactions:_Deuteration_Changes_Binding_Affinities_for_Histamine_Receptor_Ligands_ L2 - http://dx.plos.org/10.1371/journal.pone.0154002 DB - PRIME DP - Unbound Medicine ER -