Limits of Ligand Selectivity from Docking to Models: In Silico Screening for A ₁ Adenosine Receptor Antagonists

Abstract

G protein-coupled receptors (GPCRs) are attractive targets for pharmaceutical research. With the recent determination of several GPCR X-ray structures, the applicability of structure-based computational methods for ligand identification, such as docking, has increased. Yet, as only about 1% of GPCRs have a known structure, receptor homology modeling remains necessary. In order to investigate the usability of homology models and the inherent selectivity of a particular model in relation to close homologs, we constructed multiple homology models for the A ₁ adenosine receptor (A ₁AR) and docked ∼2.2 M lead-like compounds. High-ranking molecules were tested on the A ₁AR as well as the close homologs A _2AAR and A ₃AR. While the screen yielded numerous potent and novel ligands (hit rate 21% and highest affinity of 400 nM), it delivered few selective compounds. Moreover, most compounds appeared in the top ranks of only one model. These findings have implications for future screens.

Contributors

Roland Seifert: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 21 November 2012

Volume: 7

Issue: 11

Affiliations

[1 ]Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America

[2 ]Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

[3 ]Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America

Medical School of Hannover, United States of America

Author notes

* E-mail: peter.kolb@ 123456uni-marburg.de (PK); kajacobs@ 123456helix.nih.gov (KAJ)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: PK AS KAJ. Performed the experiments: PK KP ZG ACM. Analyzed the data: PK ACM KAJ. Wrote the paper: PK ACM AS KAJ.

[¤a]

Current address: Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany

[¤b]

Current address: Asuragen Inc., Austin, Texas, United States of America

Article

Publisher ID: PONE-D-12-24176

DOI: 10.1371/journal.pone.0049910

PMC ID: 3503826

PubMed ID: 23185482

License:

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Page count

Pages: 9

Funding

Funding came from a DFG Emmy-Noether Fellowship KO 4095/1-1 to PK ( www.dfg.de), a National Institutes of Health/National Institute of General Medical Sciences R01 GM083960 grant to AS ( www.nigms.nih.gov), and a National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (1ZIADK031117-24) to KAJ ( http://www2.niddk.nih.gov/NIDDKLabs/NIDDKLabsAbout.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Categories

Subject: Research Article

Subject: Biology

Subject: Biochemistry

Subject: Biochemistry Simulations

Subject: Biomacromolecule-Ligand Interactions

Subject: Drug Discovery

Subject: Biophysics

Subject: Biophysics Simulations

Subject: Computational Biology

Subject: Biochemical Simulations

Subject: Biophysic Al Simulations

Subject: Chemistry

Subject: Medicinal Chemistry

Subject: Computer Science

Subject: Computer Applications

Subject: Computer-Aided Design

Subject: Medicine

Subject: Drugs and Devices

Subject: Drug Research and Development

Subject: Drug Discovery

Subject: Physics

Subject: Biophysics

Subject: Biomacromolecule-Ligand Interactions