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Current Assessment of Docking into GPCR Crystal Structures and Homology Models: Successes, Challenges, and Guidelines

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Schrödinger, Inc., 120 West 45th Street, New York, New York, United States
*E-mail: [email protected]. Phone: 212 295 5800. Fax: 212 295 5801.
Cite this: J. Chem. Inf. Model. 2012, 52, 12, 3263–3277
Publication Date (Web):November 3, 2012
Copyright © 2012 American Chemical Society

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The growing availability of novel structures for several G protein-coupled receptors (GPCRs) has provided new opportunities for structure-based drug design of ligands against this important class of targets. Here, we report a systematic analysis of the accuracy of docking small molecules into GPCR structures and homology models using both rigid receptor (Glide SP and Glide XP) and flexible receptor (Induced Fit Docking; IFD) methods. The ability to dock ligands into different structures of the same target (cross-docking) is evaluated for both agonist and inverse agonist structures of the A2A receptor and the β1- and β2-adrenergic receptors. In addition, we have produced homology models for the β1-adrenergic, β2-adrenergic, D3 dopamine, H1 histamine, M2 muscarine, M3 muscarine, A2A adenosine, S1P1, κ-opioid, and C-X-C chemokine 4 receptors using multiple templates and investigated the ability of docking to predict the binding mode of ligands in these models. Clear correlations are observed between the docking accuracy and the similarity of the sequence of interest to the template, suggesting regimes in which docking can correctly identify ligand binding modes.

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Full RMSD results for all methods and benchmarks are available as Tables S1–S9. A comparison of the performance of all methods with and without loops is shown in Table S10. Pairwise sequence identities for the full sequences are shown in Table S11. Rigid docking example poses are provided in Figures S1 and S2. A correlation plot between docking RMSD and binding site RMSD is shown in Figure S3. This material is available free of charge via the Internet at

Accession Codes

PDB ID Codes:2VT4, 2YCW, 2Y00, 2Y02, 2Y03, 2Y04, 2RH1, 3D4S, 3NY8, 3NY9, 3NYA, 3P0G, 3PBL, 3RZE, 3UON, 4DAJ, 3EML, 3REY, 3RFM, 2YDO, 2YDV, 3QAK, 3V2Y, 3ODU, 4DHJ, 4DKL

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