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Molecular Docking Screening Using Agonist-Bound GPCR Structures: Probing the A2A Adenosine Receptor

David Rodríguez, Zhang-Guo Gao, Steven M. Moss, Kenneth A. Jacobson, Jens Carlsson
2015 Journal of Chemical Information and Modeling  
Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structurebased drug  ...  The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened  ...  We thank OpenEye Scientific Software for the use of OEChem, OMEGA, and ROCS at no cost. J.C. and D.R. participated in the European COST Action CM1207 (GLISTEN).  ... 
doi:10.1021/ci500639g pmid:25625646 pmcid:PMC4474233 fatcat:tctgqo5pk5bpxpzq5lkk5cwyby

Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold

T. Santhosh Kumar, Shilpi Mishra, Francesca Deflorian, Lena S. Yoo, Khai Phan, Miklos Kecskés, Angela Szabo, Bidhan Shinkre, Zhan-Guo Gao, William Trenkle, Kenneth A. Jacobson
2011 Bioorganic & Medicinal Chemistry Letters  
Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A(2A)AR as well as the distal  ...  Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A(2A) adenosine receptor (AR).  ...  Acknowledgments This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. We thank Dr.  ... 
doi:10.1016/j.bmcl.2010.11.082 pmid:21185184 pmcid:PMC3081901 fatcat:va6isdwsmrft5jce4nunr7y35a

Crystal structures of the A2A adenosine receptor and their use in medicinal chemistry

Kenneth A Jacobson
2013 In Silico Pharmacology  
New insights into drug design are derived from the X-ray crystallographic structures of G protein-coupled receptors (GPCRs), and the adenosine receptors (ARs) are at the forefront of this effort.  ...  The predictability of modeling based on the X-ray structures of the A 2A AR has been well demonstrated in the identification, design and modification of both known and novel AR agonists and antagonists  ...  Acknowledgements This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases.  ... 
doi:10.1186/2193-9616-1-22 pmid:24660138 pmcid:PMC3956660 fatcat:psfdrzprdjbf7axybbr4kfldfa

Structure-based drug screening for G-protein-coupled receptors

Brian K. Shoichet, Brian K. Kobilka
2012 TIPS - Trends in Pharmacological Sciences  
The past four years have seen remarkable progress in the structural biology of GPCRs, raising the possibility of applying structure-based approaches to GPCR drug discovery efforts.  ...  Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets.  ...  As in earlier docking screens against the β 2 adrenergic and the A2a adenosine receptors, the screen against the D3 receptor had a high hit rate, 23%, with affinities as good as 200 nM.  ... 
doi:10.1016/j.tips.2012.03.007 pmid:22503476 pmcid:PMC3523194 fatcat:uehc45h43netjioxuods5357ka

The impact of GPCR structures on pharmacology and structure-based drug design

Miles Congreve, Fiona Marshall
2009 British Journal of Pharmacology  
After many years of effort, recent technical breakthroughs have enabled the X-ray crystal structures of three G-protein-coupled receptors (GPCRs) (b1 and b2 adrenergic and adenosine A2a) to be solved in  ...  future. 159 986-996 Receptor activation and signalling The ligand bound to rhodopsin (11-cis retinal) is a strong inverse agonist which maintains the receptor in the completely inactive dark state.  ...  Statement of conflict of interest MC and FM are employed by Heptares Therapeutics, a company engaged in structure-based research for GPCR targets.  ... 
doi:10.1111/j.1476-5381.2009.00476.x pmid:19912230 pmcid:PMC2839258 fatcat:76c6zxz35vdyrevnbihl33qiny

Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation [article]

Ashley R. Vidad, Stephen Macaspac, Ho Leung Ng
2018 bioRxiv   pre-print
We demonstrate the effectiveness of ConDock on well-characterized GPCRs such as the beta2 adrenergic and A2A adenosine receptors.  ...  We describe our new method, ConDock, for predicting ligand binding sites in GPCRs using combined information from surface conservation and docking starting from crystal structures or homology models.  ...  For both receptors, we performed cross-docking of an agonist and inverse agonist against a crystal structure of the receptor bound to a different agonist or inverse agonist: ligands were cross-docked rather  ... 
doi:10.1101/461681 fatcat:opgwouw5j5ghnerbkcjldrzruy

Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation

Ashley Ryan Vidad, Stephen Macaspac, Ho Leung Ng
2021 PeerJ  
We demonstrate the effectiveness of ConDockSite on crystallized class A GPCRs such as the beta2 adrenergic and A2A adenosine receptors.  ...  GPCRs (G-protein coupled receptors) are the largest family of drug targets and share a conserved structure.  ...  The crystal structures used were of the A2A adenosine receptor bound to the agonist, adenosine (PDB 2ydo), the agonist, CGS21680 (PDB 4ug2), the inverse agonist, ZM241385 (PDB 5k2a), and the inverse agonist  ... 
doi:10.7717/peerj.12219 pmid:34631323 pmcid:PMC8475542 fatcat:fo6v47x7bffdtnaqbx6vza6qpq

Structure Based Inhibition of Mitochondrial Aldehyde Dehydrogenase (ALDH2) Activity

Ann C. Kimble-Hill, Hina Younus, Samy Meroueh, Thomas D. Hurley
2011 Biophysical Journal  
Using Liticon method we have calculated the activation pathway of agonist bound adenosine receptor A2A starting from its inactive state.  ...  We recently predicted the structures of D3 dopamine receptor and CXCR4 chemokine receptor as part of the competition for the assessment of computational methods in GPCR modeling (GPCR Dock 2010).  ... 
doi:10.1016/j.bpj.2010.12.1387 fatcat:tc2xi62fqja65c6ndshoyfnyc4

Customizing G Protein-Coupled Receptor Models for Structure-Based Virtual Screening

Chris de Graaf, Didier Rognan
2009 Current pharmaceutical design  
Finally, an overview of several successful structure-based screening shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands.  ...  This review will focus on the construction, refinement, and validation of G Protein-coupled receptor models for the purpose of structure-based virtual screening.  ...  Recently, crystal structures of squid rhodopsin, the beta adrenergic receptors type 1 (ADRB1) and 2 (ADRB2), the A2A adenosine receptor (AA2AR), and the ligand-free opsin (Ops*) were solved [10] [11]  ... 
doi:10.2174/138161209789824786 pmid:20028320 fatcat:e2j3rcvtenbpne3xbnspjl526a

Small Molecule HIV-1 Capsid Inhibitor Design using Hybrid Structure Based Methods

Sandhya Kortagere, Navid Madani, Marie K. Mankowski, Amy Princiotto, Kevin Anthony, Luz-Jeannette Sierra, Xiaozhao Wang, David M. Jones, Joel R. Courter, Eric Stavale, Roger Ptak, Amos B. Smith (+3 others)
2011 Biophysical Journal  
Using Liticon method we have calculated the activation pathway of agonist bound adenosine receptor A2A starting from its inactive state.  ...  We recently predicted the structures of D3 dopamine receptor and CXCR4 chemokine receptor as part of the competition for the assessment of computational methods in GPCR modeling (GPCR Dock 2010).  ... 
doi:10.1016/j.bpj.2010.12.1385 fatcat:aui4pp4w2baxpitnntf2myue2q

Recent Trends and Applications of Molecular Modeling in GPCR–Ligand Recognition and Structure-Based Drug Design

Xiaojing Yuan, Yechun Xu
2018 International Journal of Molecular Sciences  
Additionally, docking, together with more accurate free energy calculation methods, is playing an important role in the design of novel compounds targeting GPCRs.  ...  Molecular modeling techniques, especially enhanced sampling methods, have provided significant insight into the mechanism of GPCR–ligand recognition.  ...  , in structure-based design of drugs/probes targeting GPCRs.  ... 
doi:10.3390/ijms19072105 pmid:30036949 pmcid:PMC6073596 fatcat:4n5qxfikzvd27i7nl7acsdhx6u

High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks

Jonathan S Mason, Andrea Bortolato, Dahlia R Weiss, Francesca Deflorian, Benjamin Tehan, Fiona H Marshall
2013 In Silico Pharmacology  
Results: Analysis of diverse ligands binding to the adenosine A 2A receptor together with new structures for the δ/κ/μ opioid and CCR5 receptors confirmed the key role of lipophilic hotspots in driving  ...  Conclusions: The promise of full structure-based drug design (SBDD) for GPCRs is now possible using a combination of advanced experimental and computational data.  ...  Congreve for the chromone project work.  ... 
doi:10.1186/2193-9616-1-23 fatcat:jxt47ssec5bavgizayytobivge

Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs

Bryan L. Roth
2019 Nature Structural & Molecular Biology  
Over the past decade or so, a revolution in membrane-protein structural determination has clarified the molecular determinants responsible for the actions of these receptors.  ...  This Review focuses on the G protein-coupled receptors (GPCRs) that are targets of neuropsychiatric drugs and shows how insights into the structure and function of these important synaptic proteins are  ...  ACKNOWLEDGEMENTS The author thanks Wes Kroeze, PhD and the Editor for helpful editing and comments.  ... 
doi:10.1038/s41594-019-0252-8 pmid:31270468 pmcid:PMC6613815 fatcat:egusochmefa6xjx2vskalo74vm

Elucidating Time Course of Structural Changes Leading to Receptor-Ligand Complex Formation with Transient-EPR

Shatanik Mukherjee, Reinhard Seifert, Heinz-Jürgen Steinhoff, Daniel Klose, U. Benjamin Kaupp
2014 Biophysical Journal  
Once the binding domain had been unambiguously identified, we determined the binding epitopes on netrin-1 by mutational analysis, using structural information and phylogenetic conservation as guides.  ...  We probed the binding behaviour of the chimeras by surface plasmon resonance and solid phase binding assays.  ...  An initial GPR119 homology model was constructed using the adenosine A2A receptor crystal structure bound to an antagonist at 2.6Å resolution (PDB id: 3EML) as the template.  ... 
doi:10.1016/j.bpj.2013.11.2706 fatcat:2idltol7nrcwjbw7a6ffcvnxnq

Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery

R. N. V. Krishna Deepak, Ravi Kumar Verma, Yossa Dwi Hartono, Wen Shan Yew, Hao Fan
2021 Pharmaceuticals  
The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened  ...  From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology.  ...  Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/ph15010012 pmid:35056070 pmcid:PMC8779880 fatcat:cqbgiz4sj5hz5kjbd4o2z7udwy
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