title: From Homology Models to a Set of Predictive Binding Pockets-a 5-HT1AReceptor Case Study.
abstract: Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the X-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including the endogenous neurotransmitter-serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1Areceptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform. Starting from a homology template and set of known actives, the method introduces receptor flexibility via Normal Mode Analysis and Monte Carlo sampling, to generate a subset of pockets that display enriched discrimination of actives from inactives in retrospective docking. Here, we thoroughly investigated the repercussions of using different protein templates and the effect of compound selection on screening performance. Finally, the best resulting protein models were applied prospectively in a large virtual screening campaign, in which two new active compounds were identified that were chemically distinct from those described in the literature.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Warszycki
authors.affiliation: Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego , 9500 Gilman Drive, MC 0747 La Jolla, California 92093-0747, United States.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rueda
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mordalski
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Kurt
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rataj
authors.affiliation: Department of Cell Biology, National Medicines Institute , 30/34 Chełmska Street, 00-725 Warszawa, Poland.
authors.forename: Zdzisław
authors.initials: Z
authors.lastname: Chilmonczyk
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego , 9500 Gilman Drive, MC 0747 La Jolla, California 92093-0747, United States.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Andrzej J
authors.identifier: 0000-0003-1417-6333
authors.initials: AJ
authors.lastname: Bojarski
mesh_terms: D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D008024:Ligands; D044282:Receptor, Serotonin, 5-HT1A