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Performance of virtual screening against GPCR homology models: Impact of template selection and treatment of binding site plasticity


Jaiteh, Mariama; Rodríguez-Espigares, Ismael; Selent, Jana; Carlsson, Jens (2020), Performance of virtual screening against GPCR homology models: Impact of template selection and treatment of binding site plasticity, Dryad, Dataset,


Rational drug design for G protein-coupled receptors (GPCRs) is limited by the small number of available atomic resolution structures. We assessed the use of homology modeling to predict the structures of two therapeutically relevant GPCRs and strategies to improve the performance of virtual screening against modeled binding sites. Homology models of the D2 dopamine (D2R) and serotonin 5-HT2A receptors (5-HT2AR) were generated based on crystal structures of 16 different GPCRs. Comparison of the homology models to D2R and 5-HT2AR crystal structures showed that accurate predictions could be obtained, but not necessarily using the most closely related template. Assessment of virtual screening performance was based on molecular docking of ligands and decoys. The results demonstrated that several templates and multiple models based on each of these must be evaluated to identify the optimal binding site structure. Models based on aminergic GPCRs displayed ligand enrichment and there was a trend toward improved virtual screening performance with increasing binding site accuracy. The best models even displayed ligand enrichment better than that of the D2R and 5-HT2AR crystal structures. Methods to consider binding site plasticity were explored to further improve predictions. Molecular docking to ensembles of structures did not outperform the best individual binding site models, but could increase the diversity of hits from virtual screens and be advantageous for GPCR targets with few known ligands. Molecular dynamics refinement resulted in moderate improvements of structural accuracy and the virtual screening performance of snapshots was either comparable to or worse than that of the raw homology models. These results provide guidelines for successful application of structure-based ligand discovery using GPCR homology models.


This data was obtained running unrestrained molecular dynamics simulations of the the D2R and 5-HT2AR homology models with ACEMD in a hydrated POCP membrane.


Vetenskapsrådet, Award: 2017-4676

Stiftelsen för Strategisk Forskning eSSENCE

Science for Life Laboratory

Ake Wiberg Stiftelse

NEURON- ERANET, Award: AC18/00030

Instituto de Salud Carlos III FEDER, Award: PI15/00460 & PI18/00094

Goran Gustafssons Foundation

Stiftelsen för Strategisk Forskning eSSENCE

Goran Gustafssons Foundation