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

Vass, Márton and Schmidt, Éva and Horti, Ferenc and Keserű, György Miklós (2014) Virtual fragment screening on GPCRs: A case study on dopamine D3 and histamine H4 receptors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 77 (2). pp. 38-46. ISSN 0223-5234

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Abstract

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. (C) 2014 Elsevier Masson SAS. All rights reserved.

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