Function-specific virtual screening for GPCR ligands using a combined scoring method

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Function-specific virtual screening for GPCR ligands using a combined scoring method. / Kooistra, Albert J.; Vischer, Henry F.; McNaught-Flores, Daniel; Leurs, Rob; De Esch, Iwan J.P.; De Graaf, Chris.

In: Scientific Reports, Vol. 6, 28288, 24.06.2016.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Kooistra, AJ, Vischer, HF, McNaught-Flores, D, Leurs, R, De Esch, IJP & De Graaf, C 2016, 'Function-specific virtual screening for GPCR ligands using a combined scoring method', Scientific Reports, vol. 6, 28288. https://doi.org/10.1038/srep28288

APA

Kooistra, A. J., Vischer, H. F., McNaught-Flores, D., Leurs, R., De Esch, I. J. P., & De Graaf, C. (2016). Function-specific virtual screening for GPCR ligands using a combined scoring method. Scientific Reports, 6, [28288]. https://doi.org/10.1038/srep28288

Vancouver

Kooistra AJ, Vischer HF, McNaught-Flores D, Leurs R, De Esch IJP, De Graaf C. Function-specific virtual screening for GPCR ligands using a combined scoring method. Scientific Reports. 2016 Jun 24;6. 28288. https://doi.org/10.1038/srep28288

Author

Kooistra, Albert J. ; Vischer, Henry F. ; McNaught-Flores, Daniel ; Leurs, Rob ; De Esch, Iwan J.P. ; De Graaf, Chris. / Function-specific virtual screening for GPCR ligands using a combined scoring method. In: Scientific Reports. 2016 ; Vol. 6.

Bibtex

@article{6eb5c5187ba54eb7bec4033542be86d2,
title = "Function-specific virtual screening for GPCR ligands using a combined scoring method",
abstract = "The ability of scoring functions to correctly select and rank docking poses of small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe a virtual screening method that combines an energy-based docking scoring function with a molecular interaction fingerprint (IFP) to identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. The consensus scoring method is prospectively evaluated by: 1) the discovery of chemically novel, fragment-like, high affinity histamine H1 receptor (H1R) antagonists/inverse agonists, 2) the selective structure-based identification of {\ss}2-adrenoceptor ({\ss}2R) agonists, and 3) the experimental validation and comparison of the combined and individual scoring approaches. Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H1R and {\ss}2R ligands and the selection of an optimal {\ss}-adrenoceptor crystal structure for the discrimination between {\ss}2R agonists and antagonists. The consensus approach resulted in the experimental validation of 53% of the {\ss}2R and 73% of the H1R virtual screening hits with up to nanomolar affinities and potencies. The selective identification of {\ss}2R agonists shows the possibilities of structure-based prediction of GPCR ligand function by integrating protein-ligand binding mode information.",
author = "Kooistra, {Albert J.} and Vischer, {Henry F.} and Daniel McNaught-Flores and Rob Leurs and {De Esch}, {Iwan J.P.} and {De Graaf}, Chris",
year = "2016",
month = jun,
day = "24",
doi = "10.1038/srep28288",
language = "English",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Function-specific virtual screening for GPCR ligands using a combined scoring method

AU - Kooistra, Albert J.

AU - Vischer, Henry F.

AU - McNaught-Flores, Daniel

AU - Leurs, Rob

AU - De Esch, Iwan J.P.

AU - De Graaf, Chris

PY - 2016/6/24

Y1 - 2016/6/24

N2 - The ability of scoring functions to correctly select and rank docking poses of small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe a virtual screening method that combines an energy-based docking scoring function with a molecular interaction fingerprint (IFP) to identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. The consensus scoring method is prospectively evaluated by: 1) the discovery of chemically novel, fragment-like, high affinity histamine H1 receptor (H1R) antagonists/inverse agonists, 2) the selective structure-based identification of ß2-adrenoceptor (ß2R) agonists, and 3) the experimental validation and comparison of the combined and individual scoring approaches. Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H1R and ß2R ligands and the selection of an optimal ß-adrenoceptor crystal structure for the discrimination between ß2R agonists and antagonists. The consensus approach resulted in the experimental validation of 53% of the ß2R and 73% of the H1R virtual screening hits with up to nanomolar affinities and potencies. The selective identification of ß2R agonists shows the possibilities of structure-based prediction of GPCR ligand function by integrating protein-ligand binding mode information.

AB - The ability of scoring functions to correctly select and rank docking poses of small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe a virtual screening method that combines an energy-based docking scoring function with a molecular interaction fingerprint (IFP) to identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. The consensus scoring method is prospectively evaluated by: 1) the discovery of chemically novel, fragment-like, high affinity histamine H1 receptor (H1R) antagonists/inverse agonists, 2) the selective structure-based identification of ß2-adrenoceptor (ß2R) agonists, and 3) the experimental validation and comparison of the combined and individual scoring approaches. Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H1R and ß2R ligands and the selection of an optimal ß-adrenoceptor crystal structure for the discrimination between ß2R agonists and antagonists. The consensus approach resulted in the experimental validation of 53% of the ß2R and 73% of the H1R virtual screening hits with up to nanomolar affinities and potencies. The selective identification of ß2R agonists shows the possibilities of structure-based prediction of GPCR ligand function by integrating protein-ligand binding mode information.

UR - http://www.scopus.com/inward/record.url?scp=84975721733&partnerID=8YFLogxK

U2 - 10.1038/srep28288

DO - 10.1038/srep28288

M3 - Journal article

C2 - 27339552

AN - SCOPUS:84975721733

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 28288

ER -

ID: 199352130