A QM protein-ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)

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dc.authoridYurtsever, Mine/0000-0001-6504-7182
dc.authoridStein, Matthias/0000-0001-7793-0052
dc.authoridEkhteiari Salmas, Ramin/0000-0003-3888-5070
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.authorwosidDurdagi, Serdar/B-6862-2009
dc.authorwosidYurtsever, Mine/O-3748-2014
dc.authorwosidStein, Matthias/A-2865-2011
dc.authorwosidEkhteiari Salmas, Ramin/J-6401-2016
dc.authorwosidDurdagi, Serdar/J-1904-2018
dc.contributor.authorSalmas, Ramin Ekhteiari
dc.contributor.authorIs, Yusuf Serhat
dc.contributor.authorDurdagi, Serdar
dc.contributor.authorStein, Matthias
dc.contributor.authorYurtsever, Mine
dc.date.accessioned2024-06-13T20:18:09Z
dc.date.available2024-06-13T20:18:09Z
dc.date.issued2018
dc.departmentİstanbul Gedik Üniversitesi
dc.description.abstractThe dopamine D2 Receptor (D2R) is a member of the G-Protein-Coupled Receptor family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used antipsychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine. Due to their significant side effects and non-selective profiles, the discovery of novel drugs has become a challenge for researchers working in this field. Recently, our group has focused on the interactions of these drug molecules in the active site of the D2R using different in silico approaches. We here compare the performances of different approaches in estimating the drug binding affinities using quantum chemical approaches. Conformations of drug molecules (ligands) at the binding site of the D2R taken from the preliminary docking studies and molecular dynamics simulations were used to generate protein-ligand interaction models. In a first approach, the BSSE-corrected interaction energies of the ligands with the most critical amino acid Asp114 and with the other amino acids closest to ligands in the binding cavity were calculated separately by density functional theory method in implicit water environment at the M06-2X/6-31 g(d,p) level of the theory. In a second approach, ligand binding affinities were calculated by taking into consideration not only the interaction energies but also deformation and desolvation energies of ligands with surrounding amino acid residues, in a radius of 5 angstrom of the protein-bound ligand. The quantum mechanically obtained results were compared with the experimentally obtained binding affinity values. We concluded that although H-bond interactions of ligands with Asp114 are the most dominant interaction in the binding site, if van der Waals and steric interactions of ligands which have cumulative effect on the ligand binding are not included in the calculations, the interaction energies are overestimated.
dc.description.sponsorshipMax Planck Society for the Advancement of Science; 'Center for Dynamic Systems: Systems Engineering' (an excellence initiative by Saxony-Anhalt); 'Center for Dynamic Systems: Systems Engineering' (an excellence initiative by ERDF); Research Fund of Istanbul Technical University; National Center for High Performance Computing of Turkey (UHEM) [5004452017]
dc.description.sponsorshipThis work was supported by the Max Planck Society for the Advancement of Science, the 'Center for Dynamic Systems: Systems Engineering' (an excellence initiative by Saxony-Anhalt and ERDF) and the Research Fund of Istanbul Technical University. Computing resources are provided by the National Center for High Performance Computing of Turkey (UHEM) under the Grant Number 5004452017.
dc.identifier.doi10.1080/07391102.2017.1365772
dc.identifier.endpage2677
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.issue10
dc.identifier.pmid28805144
dc.identifier.scopus2-s2.0-85028552846
dc.identifier.scopusqualityQ2
dc.identifier.startpage2668
dc.identifier.urihttps://doi.org/10.1080/07391102.2017.1365772
dc.identifier.urihttps://hdl.handle.net/11501/1247
dc.identifier.volume36
dc.identifier.wosWOS:000445170900016
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherTaylor & Francis Inc
dc.relation.ispartofJournal of Biomolecular Structure & Dynamics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectComputer Aided Drug Design
dc.subjectProtein-Ligand Interactions
dc.subjectQuantum Mechanics Calculations
dc.subjectGpcrs
dc.subjectLigand Binding Affinities
dc.subjectDft
dc.subjectMembrane-Spanning Segment
dc.subjectBinding-Site
dc.subjectDensity Functionals
dc.subjectResidues
dc.subjectStates
dc.subjectDispersion
dc.subjectMultiple
dc.subjectGpcrs
dc.subjectM06
dc.titleA QM protein-ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)
dc.typeArticle

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