Extended template-based modeling and evaluation method using consensus of binding mode of GPCRs for virtual screening

Journal of Chemical Information and Modeling
Miwa Sato, Takatsugu Hirokawa

Abstract

G-protein-coupled receptors (GPCRs) are a pharmaceutically important protein family because they mediate numerous physiological functions. The crystal structures of several GPCR subtypes have been determined recently, encouraging efforts to apply structure-based virtual screening (SBVS) along with ligand-based virtual screening (LBVS) to improve the hit rate of active ligands from large chemical libraries. Three-dimensional models are also necessary for GPCR targets whose structures are unknown. Current challenges include the selection of structural templates from available structurally known GPCRs to use for accurate modeling and understanding the diversity of sites recognizing distinct ligands. We have developed and validated an extended template-based modeling and evaluation method for SBVS. Models were generated using a fragmental template procedure in addition to typical template-based modeling methods. The reliability of the models was evaluated using a virtual screening test with known active ligands and decoys and the consensus of the binding mode using the protein-ligand interaction fingerprint (PLIF) derived from the results of docking simulations. This novel workflow was applied to three targets with known structures...Continue Reading

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Citations

Oct 21, 2016·Current Opinion in Pharmacology·Márton VassChris de Graaf
Oct 6, 2016·Expert Opinion on Drug Discovery·Róbert Kiss, György M Keserű
Jul 30, 2019·Journal of Molecular Recognition : JMR·Carlos Z Gómez-CastroItzia I Padilla-Martínez
Oct 6, 2018·Journal of Cheminformatics·Anita RáczKároly Héberger
Sep 19, 2019·European Journal of Medicinal Chemistry·Giuseppe RomeoMaria Nunziata Modica
Apr 8, 2015·Journal of Chemical Information and Modeling·Albert J KooistraChris de Graaf

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