Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor

Enade P. Istyastono, Albert J. Kooistra, Henry F. Vischer, Martien Kuijer, Luc Roumen, Saskia Nijmeijer, Rogier A. Smits, Iwan J P De Esch, Rob Leurs, C. de Graaf

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

We have explored the possibilities and challenges of structure-based virtual screening (SBVS) against the human histamine H4 receptor (H4R), a key player in inflammatory responses. Several SBVS strategies, employing different H4R ligand conformations, were validated and optimized with respect to their ability to discriminate small fragment-like H4R ligands from true inactive fragments, and compared to ligand-based virtual screening (LBVS) approaches. SBVS studies with a molecular interaction fingerprint (IFP) scoring method enabled the identification of H4R ligands that were not identified in LBVS runs, demonstrating the scaffold hopping potential of combining molecular docking and IFP scoring. Retrospective VS evaluations against H4R homology models based on the histamine H1 receptor (H1R) crystal structure did not give higher enrichments of H4R ligands than H4R models based on the beta-2 adrenergic receptor (β2R). Complementary prospective SBVS studies against β2R-based and H1R-based H4R homology models led to the discovery of different new fragment-like H4R ligand chemotypes. Of the 37 tested compounds, 9 fragments (representing 5 different scaffolds) had affinities between 0.14 and 6.3 μM at the H4R.

Original languageEnglish
Pages (from-to)1003-1017
Number of pages15
JournalMedChemComm
Volume6
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

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Histamine Receptors
GTP-Binding Proteins
Histamine
Screening
Ligands
Histamine H1 Receptors
Dermatoglyphics
Scaffolds
Adrenergic beta-2 Receptors
Molecular interactions
Adrenergic Receptors
Conformations
Research Design
Crystal structure

Cite this

Istyastono, E. P., Kooistra, A. J., Vischer, H. F., Kuijer, M., Roumen, L., Nijmeijer, S., ... de Graaf, C. (2015). Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor. MedChemComm, 6(6), 1003-1017. https://doi.org/10.1039/c5md00022j
Istyastono, Enade P. ; Kooistra, Albert J. ; Vischer, Henry F. ; Kuijer, Martien ; Roumen, Luc ; Nijmeijer, Saskia ; Smits, Rogier A. ; De Esch, Iwan J P ; Leurs, Rob ; de Graaf, C. / Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor. In: MedChemComm. 2015 ; Vol. 6, No. 6. pp. 1003-1017.
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Istyastono, EP, Kooistra, AJ, Vischer, HF, Kuijer, M, Roumen, L, Nijmeijer, S, Smits, RA, De Esch, IJP, Leurs, R & de Graaf, C 2015, 'Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor' MedChemComm, vol. 6, no. 6, pp. 1003-1017. https://doi.org/10.1039/c5md00022j

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor. / Istyastono, Enade P.; Kooistra, Albert J.; Vischer, Henry F.; Kuijer, Martien; Roumen, Luc; Nijmeijer, Saskia; Smits, Rogier A.; De Esch, Iwan J P; Leurs, Rob; de Graaf, C.

In: MedChemComm, Vol. 6, No. 6, 01.06.2015, p. 1003-1017.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Roumen, Luc

AU - Nijmeijer, Saskia

AU - Smits, Rogier A.

AU - De Esch, Iwan J P

AU - Leurs, Rob

AU - de Graaf, C.

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