Ligand discovery from a dopamine D3 receptor homology model and crystal structure
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Open Access
- 18 September 2011
- journal article
- research article
- Published by Springer Nature in Nature Chemical Biology
- Vol. 7 (11) , 769-778
- https://doi.org/10.1038/nchembio.662
Abstract
A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities. G protein–coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery increased. Unfortunately, for most GPCRs no experimental structures are available. The determination of the D3 receptor structure and the challenge to the community to predict it enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities ranging from 0.2 to 3.1 μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities ranging from 0.3 to 3.0 μM. One of the new ligands from the homology model screen was optimized for affinity to 81 nM. The feasibility of docking screens against modeled GPCRs more generally is considered.Keywords
This publication has 77 references indexed in Scilit:
- Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 AssessmentStructure, 2011
- Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain InhibitorsJournal of Medicinal Chemistry, 2010
- Structure-Based Discovery of A2AAdenosine Receptor LigandsJournal of Medicinal Chemistry, 2010
- Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor AntagonistsJournal of Medicinal Chemistry, 2010
- GPCR 3D homology models for ligand screening: Lessons learned from blind predictions of adenosine A2a receptor complexProteins-Structure Function and Bioinformatics, 2009
- Automated Docking Screens: A Feasibility StudyJournal of Medicinal Chemistry, 2009
- N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor AntagonistsJournal of Medicinal Chemistry, 2009
- Structure of a β1-adrenergic G-protein-coupled receptorNature, 2008
- How many drug targets are there?Nature Reviews Drug Discovery, 2006
- Benchmarking Sets for Molecular DockingJournal of Medicinal Chemistry, 2006