Virtual fragment screening on GPCRs: A case study on dopamine D3 and histamine H4 receptors

•A library of 12,905 fragments was virtually screened by docking against two GPCRs.•The D3 X-ray structure, a H4 homology model and representative frames for both receptors from MD were used.•Single structure and ensemble docking hit rates ranged from 16% to 32%.•Overlap between hit sets was low, methodologies were complementary.•Structural background of hit rates was analyzed.

Prospective structure based virtual fragment screening methodologies on two GPCR targets namely the dopamine D3 and the histamine H4 receptors with a library of 12,905 fragments were evaluated. Fragments were docked to the X-ray structure and the homology model of the D3 and H4 receptors, respectively. Representative receptor conformations for ensemble docking were obtained from molecular dynamics trajectories. In vitro confirmed hit rates ranged from 16% to 32%. Hits had high ligand efficiency (LE) values in the range of 0.31–0.74 and also acceptable lipophilic efficiency. The X-ray structure, the homology model and structural ensembles were all found suitable for docking based virtual screening of fragments against these GPCRs. However, there was little overlap among different hit sets and methodologies were thus complementary to each other.

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