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

ABSTRACT: 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(1)R) 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(1)R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 ?M 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.

SUBMITTER: de Graaf C

PROVIDER: S-EPMC3228891 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

de Graaf Chris C Kooistra Albert J AJ Vischer Henry F HF Katritch Vsevolod V Kuijer Martien M Shiroishi Mitsunori M Iwata So S Shimamura Tatsuro T Stevens Raymond C RC de Esch Iwan J P IJ Leurs Rob R

Journal of medicinal chemistry 20111107 23

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(1)R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fi ...[more]

PMID: 22007643

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Project description:AimTo discover novel ligands of estrogen receptor (ER) β using pharmacophore mapping and structure-based screening.MethodsA computer-aided strategy combining pharmacophore mapping and structure-based screening was used to screen the Maybridge and Enamine databases. Yeast two-hybrid (Y2H) assay was used to detect the activity and selectivity of the chosen compounds. The transcriptional activities of the chosen compounds were demonstrated with luciferase reporter assays. The anti-proliferative effects of ER antagonists against MCF-7 and MDA-MB-231 breast cancer cells were examined using MTT assay, and the mechanisms of action were analyzed with flow cytometry analysis and Western blotting.ResultsThrough in silico screen, 95 compounds were chosen for testing in Y2H assay, which led to 20 potent ligands, including 10 agonists, 8 antagonists and 2 partial agonists with EC50 or IC50 values at μmol/L. Furthermore, 6 agonists exhibited absolute selectivity for ERβ, and 3 agonists showed higher selectivity for ERβ. The agonists 1g and 1h (10, 25, and 50 μmol/L) dose-dependently increased ER transcriptional activities, whereas the antagonists 2a and 2d (10, 25, and 50 μmol/L) caused dose-dependent inhibition on the activities. The antagonists and partial agonists at 100 μmol/L suppressed the proliferation of ERα positive MCF-7 cells and ERβ positive MDA-MB-231 cells, but were more effective against MDA-MB-231 cells. Treatment of MDA-MB-231 cells with antagonists 2a and 2d (25 and 50 μmol/L) dose-dependently increased the population of cells in the S phase. Both 2a and 2d treatment dose-dependently decreased the expression levels of cyclin A and CDK2. Meanwhile, the downregulation of cyclin E was only caused by 2d, while 2a treatment did not cause significant changes in the protein levels of cyclin E.ConclusionThe selective ligands discovered in this study are promising drug candidates to be used as molecular probes to explore the differences between ERα and ERβ.

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

Publications

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

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