title: Dynamics and structural determinants of ligand recognition of the 5-HT6 receptor.
abstract: In order to identify molecular models of the human 5-HT6 receptor suitable for virtual screening, homology modeling and membrane-embedded molecular dynamics simulations were performed. Structural requirements for robust enrichment were assessed by an unbiased chemometric analysis of enrichments from retrospective virtual screening studies. The two main structural features affecting enrichment are the outward movement of the second extracellular loop and the formation of a hydrophobic cavity deep in the binding site. These features appear transiently in the trajectories and furthermore the stretches of uniformly high enrichment may only last 4-10 ps. The formation of the inner hydrophobic cavity was also linked to the active-like to inactive-like transition of the receptor, especially the so-called connector region. The best structural models provided significant and robust enrichment over three independent ligand sets.
authors.affiliation: Discovery Chemistry, Gedeon Richter Plc., Gyömrői út 19-21, Budapest, 1103, Hungary.|Division of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Márton
authors.initials: M
authors.lastname: Vass
authors.affiliation: Department of Chemical Informatics, Faculty of Education, University of Szeged, Boldogasszony sgt. 6, Szeged, 6725, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Jójárt
authors.affiliation: MTA SZTE Supramolecular and Nanostructured Materials Research Group, Hungarian Academy of Sciences, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Bogár
authors.affiliation: MTA SZTE Supramolecular and Nanostructured Materials Research Group, Hungarian Academy of Sciences, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary.|Department of Theoretical Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Gábor
authors.initials: G
authors.lastname: Paragi
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
authors.affiliation: Discovery Chemistry, Gedeon Richter Plc., Gyömrői út 19-21, Budapest, 1103, Hungary. akos.tarcsay@gmail.com.|ChemAxon Ltd., Záhony Str. 7, Budapest, 1031, Hungary. akos.tarcsay@gmail.com.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Tarcsay
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor
keywords: 5-HT6 receptor; Docking; Enrichment; Molecular dynamics; Virtual screening