Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor

Chris De Graaf, Albert J. Kooistra, Henry F. Vischer, Vsevolod Katritch, Martien Kuijer, Mitsunori Shiroishi, So Iwata, Tatsuro Shimamura, Raymond C. Stevens, Iwan J.P. De Esch, Rob Leurs

研究成果: ジャーナルへの寄稿記事

157 引用 (Scopus)

抄録

The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) have opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening protocol against the recently determined human histamine H 1 receptor (H 1R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≥22 heavy atoms) H 1R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space.

元の言語英語
ページ(範囲)8195-8206
ページ数12
ジャーナルJournal of Medicinal Chemistry
54
発行部数23
DOI
出版物ステータス出版済み - 12 8 2011

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Histamine
G-Protein-Coupled Receptors
Ligands
Computer Simulation
Molecular Docking Simulation
Dermatoglyphics
Proteins
Research Design

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

これを引用

De Graaf, C., Kooistra, A. J., Vischer, H. F., Katritch, V., Kuijer, M., Shiroishi, M., ... Leurs, R. (2011). Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor. Journal of Medicinal Chemistry, 54(23), 8195-8206. https://doi.org/10.1021/jm2011589

Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor. / De Graaf, Chris; Kooistra, Albert J.; Vischer, Henry F.; Katritch, Vsevolod; Kuijer, Martien; Shiroishi, Mitsunori; Iwata, So; Shimamura, Tatsuro; Stevens, Raymond C.; De Esch, Iwan J.P.; Leurs, Rob.

:: Journal of Medicinal Chemistry, 巻 54, 番号 23, 08.12.2011, p. 8195-8206.

研究成果: ジャーナルへの寄稿記事

De Graaf, C, Kooistra, AJ, Vischer, HF, Katritch, V, Kuijer, M, Shiroishi, M, Iwata, S, Shimamura, T, Stevens, RC, De Esch, IJP & Leurs, R 2011, 'Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor', Journal of Medicinal Chemistry, 巻. 54, 番号 23, pp. 8195-8206. https://doi.org/10.1021/jm2011589
De Graaf C, Kooistra AJ, Vischer HF, Katritch V, Kuijer M, Shiroishi M その他. Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor. Journal of Medicinal Chemistry. 2011 12 8;54(23):8195-8206. https://doi.org/10.1021/jm2011589
De Graaf, Chris ; Kooistra, Albert J. ; Vischer, Henry F. ; Katritch, Vsevolod ; Kuijer, Martien ; Shiroishi, Mitsunori ; Iwata, So ; Shimamura, Tatsuro ; Stevens, Raymond C. ; De Esch, Iwan J.P. ; Leurs, Rob. / Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor. :: Journal of Medicinal Chemistry. 2011 ; 巻 54, 番号 23. pp. 8195-8206.
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