Journal ArticleDOI
Current Assessment of Docking into GPCR Crystal Structures and Homology Models: Successes, Challenges, and Guidelines
Thijs Beuming,Woody Sherman +1 more
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TLDR
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.Abstract:
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 dock...read more
Citations
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Journal ArticleDOI
Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments
TL;DR: It is shown that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets.
Journal ArticleDOI
Improvements, trends, and new ideas in molecular docking: 2012-2013 in review.
TL;DR: This review discusses the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline.
Journal ArticleDOI
Protein-ligand docking in the new millennium--a retrospective of 10 years in the field
Sérgio F. Sousa,António J. M. Ribeiro,João Coimbra,Rui P. P. Neves,Silvia A. Martins,N.S.H.N. Moorthy,Pedro A. Fernandes,Maria J. Ramos +7 more
TL;DR: Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in this field.
Journal ArticleDOI
MT1 and MT2 Melatonin Receptors: Ligands, Models, Oligomers, and Therapeutic Potential
Darius P. Zlotos,Ralf Jockers,Ralf Jockers,Ralf Jockers,Erika Cecon,Silvia Rivara,Paula A. Witt-Enderby +6 more
TL;DR: Recent advances in the field focusing on high-affinity agonists and antagonists and those displaying selectivity toward MT1 and MT2 receptors are reviewed and the current status in the emerging field of melatonin receptor oligomerization is critically discussed.
Journal ArticleDOI
Modelling three-dimensional protein structures for applications in drug design
Tobias Schmidt,Tobias Schmidt,Andreas Bergner,Andreas Bergner,Torsten Schwede,Torsten Schwede +5 more
TL;DR: This review outlines recent methodical advances in homology modelling, with a focus on those techniques that necessitate consideration of ligand binding and basic guidelines for good modelling practice are provided.
References
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Clustal W and Clustal X version 2.0
Mark A. Larkin,Gordon Blackshields,Nigel P. Brown,R. Chenna,Paul A. McGettigan,Hamish McWilliam,Franck Valentin,Iain M. Wallace,Andreas Wilm,Rodrigo Lopez,J.D. Thompson,Toby J. Gibson,Desmond G. Higgins +12 more
TL;DR: The Clustal W and ClUSTal X multiple sequence alignment programs have been completely rewritten in C++ to facilitate the further development of the alignment algorithms in the future and has allowed proper porting of the programs to the latest versions of Linux, Macintosh and Windows operating systems.
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Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.
Richard A. Friesner,Jay L. Banks,Robert B. Murphy,Thomas A. Halgren,Jasna Klicic,Daniel T. Mainz,Matthew P. Repasky,Eric H. Knoll,Mee Shelley,Jason K. Perry,David E. Shaw,Perry Francis,Peter S Shenkin +12 more
TL;DR: Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand to find the best docked pose using a model energy function that combines empirical and force-field-based terms.
Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Journal ArticleDOI
Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.
Thomas A. Halgren,Robert B. Murphy,Richard A. Friesner,Hege S. Beard,Leah L. Frye,W. Thomas Pollard,Jay L. Banks +6 more
TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
Journal ArticleDOI
Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
Richard A. Friesner,Robert B. Murphy,Matthew P. Repasky,Leah L. Frye,Jeremy R. Greenwood,Thomas A. Halgren,Paul C. Sanschagrin,Daniel T. Mainz +7 more
TL;DR: Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
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