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Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands

Zhijun Wu, Victor J. Hruby
2019 ACS Omega  
Opioid ligands are a large group of G-protein-coupled receptor ligands possessing high structural diversity, along with complicated structure-activity relationships (SARs).  ...  To better understand their structural correlations as well as the related SARs, we developed the innovative template-based alignment modeling in our recent studies on a variety of opioid ligands.  ...  Understanding their structural correlation will not only help for the elucidation of the structureactivity relationships (SARs) of opioid ligands but can also greatly aid the discovery of new opioid drugs  ... 
doi:10.1021/acsomega.9b02244 pmid:31656918 pmcid:PMC6812133 fatcat:2tnlzepk7fcuxc7ruipoxg7dce

Computer modeling of human delta opioid receptor

F Sapundzhi, T Dzimbova, N Pencheva, P Milanov
2012 EMBnet journal  
The development of selective agonists of δ-opioid receptor as well as the model of interaction of ligands with this receptor is the subjects of increased interest.  ...  In the absence of crystal structures of opioid receptors, 3D homology models with different templates have been reported in the literature.  ...  Colors of the backbone based on the secondary structure information: Table 2 . 2 Values of IC 50 , K A and e rel obtained in mouse vas deferens by in vitro assay [8] Ligand IC 50 (nM) K A (nM) e  ... 
doi:10.14806/ej.18.a.446 fatcat:3ll7snyqebghpiwneho263spkm

Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism

Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Zhijun Wu, Justin LaVigne, Gabriella Molnar, Dagmara Tymecka, Aleksandra Misicka, John M. Streicher, Victor J. Hruby, Frank Porreca
2021 Biomedicines  
Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist  ...  Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy  ...  Acknowledgments: The present work was performed in partial fulfillment for the doctoral degree for M.R. Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/biomedicines9060625 pmid:34072734 fatcat:e52cyy644fhx3m3wglrxv4odiy

Biological and Conformational Evaluation of Bifunctional Compounds for Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists Possessing Two Penicillamines

Takashi Yamamoto, Padma Nair, Neil E. Jacobsen, Vinod Kulkarni, Peg Davis, Shou-wu Ma, Edita Navratilova, Henry I. Yamamura, Todd W. Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby
2010 Journal of Medicinal Chemistry  
The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional  ...  activities as well as its significant delta-opioid selectivity.  ...  Magdalena Kaczmarska for culturing cells, and the University of Arizona Mass Spectrometry Facility for the mass spectral measurements. We express appreciation to Ms.  ... 
doi:10.1021/jm100157m pmid:20617791 pmcid:PMC2943425 fatcat:4gzg66fzkbbzbm7tvv4si4e64e

Molecular Details of the Activation of the μ Opioid Receptor

Jihyun Shim, Andrew Coop, Alexander D. MacKerell
2013 Journal of Physical Chemistry B  
Molecular details of μ opioid receptor activations were obtained using molecular dynamics simulations of the receptor in the presence of 3 agonists, 3 antagonists, a partial agonist and on the constitutively  ...  Agonists have a higher probability of direct interactions of their basic nitrogen (N) with Asp147 as compared to antagonists, indicating that direct ligand-Asp147 interactions modulate activation.  ...  Acknowledgments Financial support from the NIH (DA13583 and DA19634) and computational support from the XSEDE supercomputing consortium and the Computer-Aided Drug Design Center, School of Pharmacy, University  ... 
doi:10.1021/jp404238n pmid:23758404 pmcid:PMC3735350 fatcat:zu7vgjo435a65c76wrevepylsy

Discovery of a Potent and Efficacious Peptide Derivative for δ/μ Opioid Agonist/Neurokinin 1 Antagonist Activity with a 2′,6′-Dimethyl-l-Tyrosine: In vitro, In vivo, and NMR-Based Structural Studies

Takashi Yamamoto, Padma Nair, Tally M. Largent-Milnes, Neil E. Jacobsen, Peg Davis, Shou-Wu Ma, Henry I. Yamamura, Todd W. Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby
2011 Journal of Medicinal Chemistry  
Multivalent ligands with delta/mu opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced  ...  The NMR structural analysis suggested that Dmt 1 incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus), and simultaneously shifts the orientation of the  ...  Magdalena Kaczmarska for culturing cells, and the University of Arizona Mass Spectrometry Facility for the mass spectra measurements. We express appreciation to Ms.  ... 
doi:10.1021/jm101023r pmid:21366266 pmcid:PMC3090346 fatcat:pg3oostm5bebvktjdw6zybjlm4

Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

Michal Kolinski, Slawomir Filipek
2009 The Open Structural Biology Journal  
To investigate the relationship between the final movements of a ligand in a receptor binding site and the first steps of the activation process in OR and OR opioid receptors we chose a set of rigid ligands  ...  with the structural motif of tyramine.  ...  To study the final movements of the ligand in the binding site and the concurrent activation steps of opioid receptors it was necessary to use opioid receptor models based on the crystal structure of an  ... 
doi:10.2174/1874199100903010051 fatcat:5r6wgzeuhzdl7je5ppmoev3ubi

Molecular modelling of the ORL1 receptor and its complex with nociceptin

C. M. Topham, L. Mouledous, G. Poda, B. Maigret, J. C. Meunier
1998 Protein Engineering Design & Selection  
Keywords: molecular modelling/G-protein coupled receptor/ opioid receptor like 1 (ORL1) receptor/neuropeptide/nociceptin/structure-activity relationships C.M.Topham et al.  ...  The functional roles of the EL2 loop and the conserved N-terminal tetrapeptide opioid 'message' binding site are discussed in the context of the different structural requirements of the ORL1 and κ-opioid  ...  Acknowledgements We thank Dan Donnelly for making available his PERSCAN suite of programs, N.Srinivasan for MODIP, and John Overington for the supply of a pre-release of the Homologous Structure Alignment  ... 
doi:10.1093/protein/11.12.1163 pmid:9930666 fatcat:3mdfbrxzwbdfpfntqzkox4b454

Conformational analysis of the endogenous μ-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling

Brent L. Podlogar, M.Germana Paterlini, David M. Ferguson, Gregory C. Leo, David A. Demeter, Frank K. Brown, Allen B. Reitz
1998 FEBS Letters  
To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques  ...  Structural comparison of the cis-and trans-configurations with morphine and selective W Wpeptide ligands PL-017 and D-TIPP, as well as the N N-selective peptide ligands TIPP (N N-antagonist, W W-agonist  ...  In addition, all aspects of the molecular dynamics simulations and structures are available upon request.  ... 
doi:10.1016/s0014-5793(98)01202-2 pmid:9849868 fatcat:mi5wpeh445ag7mrkcndf6anday

Structure-Based Virtual Screening of the Nociceptin Receptor: Hybrid Docking and Shape-Based Approaches for Improved Hit Identification

Pankaj R. Daga, Willma E. Polgar, Nurulain T. Zaveri
2014 Journal of Chemical Information and Modeling  
Given the structureactivity relationships for known NOP ligands, we developed a hybrid method that combines a structure-based and ligand-based approach, utilizing the active-state NOP receptor as well  ...  The antagonist-bound crystal structure of the nociceptin receptor (NOP), from the opioid receptor family, was recently reported along with those of the other opioid receptors bound to opioid antagonists  ...  The extensive structureactivity relationship (SAR) data on the triazaspirodecanone series of NOP ligands available in the literature was used to define four pharmacophoric features represented in the  ... 
doi:10.1021/ci500291a pmid:25148595 pmcid:PMC4210177 fatcat:zxom2qnpobaunndmpnshvobrgi

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors

K. A. Jacobson, S. Costanzi
2012 Molecular Pharmacology  
Molecular modeling, informed by supporting information from site-directed mutagenesis and structure-activity relationships, has been validated as a useful tool to extend structural insights to related  ...  These high-resolution structures have greatly increased our understanding of ligand recognition and receptor activation.  ...  Molecular modeling, informed by supporting information from site-directed mutagenesis and structure activity relationships, has been validated as a useful tool to extend structural insights to related  ... 
doi:10.1124/mol.112.079335 pmid:22695719 pmcid:PMC3422707 fatcat:bey24gcs4bdgdpsoqbmdpbgxui

In silico design of novel probes for the atypical opioid receptor MRGPRX2

Katherine Lansu, Joel Karpiak, Jing Liu, Xi-Ping Huang, John D McCorvy, Wesley K Kroeze, Tao Che, Hiroshi Nagase, Frank I Carroll, Jian Jin, Brian K Shoichet, Bryan L Roth
2017 Nature Chemical Biology  
To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found many opioid compounds activated MRGPRX2, including (−)-and (+)-morphine, hydrocodone, sinomenine, dextromethorphan and the  ...  The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch.  ...  Homology Modeling The alignment for the construction of the MRGPRX2 models was generated using PROMALS3D 54 , and homology models were built with MODELLER-9v8 27 using the crystal structure of the κ-opioid  ... 
doi:10.1038/nchembio.2334 pmid:28288109 pmcid:PMC5391270 fatcat:lpxngw3xznfxjeb2cx74ctkol4

Methods for the Development of In Silico GPCR Models [chapter]

Paula Morales, Dow P. Hurst, Patricia H. Reggio
2017 Methods in Enzymology  
In this context, we aim to develop a homology model that helps us to elucidate the structural determinants governing ligand-receptor interactions at GPR3.  ...  In this chapter, we detail the methods and rationale behind the construction of the GPR3 active and inactive state models.  ...  Binding site anchoring interactions within the receptor for each ligand should be consistent with mutational and SAR (structure-activity relationships) data.  ... 
doi:10.1016/bs.mie.2017.05.005 pmid:28750813 pmcid:PMC5809125 fatcat:lazxveqorralvkr5dxnnd6chfa

A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist

Nidhi Singh, Gwénaël Chevé, David M. Ferguson, Christopher R. McCurdy
2006 Journal of Computer-Aided Molecular Design  
The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model.  ...  The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model.  ...  Simultaneously, structure-activity relationships (SAR) among available ligands for a given receptor may afford equivalent pharmacophores.  ... 
doi:10.1007/s10822-006-9067-x pmid:17009091 fatcat:aoeqek44cber3pp2uvcoo5evba

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists†,‡

Irina D. Pogozheva, Biao-Xin Chai, Andrei L. Lomize, Tung M. Fong, David H. Weinberg, Ravi P. Nargund, Michael W. Mulholland, Ira Gantz, Henry I. Mosberg
2005 Biochemistry  
Subsequently, a complex of hMCR4 with its linear peptide agonists, α-MSH and NDP-MSH (36) was calculated assuming the structural overlap of pharmacophoric elements of peptide and nonpeptide ligands.  ...  By contrast, binding affinity and potency of the linear peptide agonist NDP-MSH were substantially reduced only in D126A and H264A mutants. 3D models of receptor-ligand complexes with their agonists were  ...  Acknowledgment The authors are grateful to Dr. Jarl E.S. Wikberg for the coordinates of the crystal structure of THIQ, described in a recent paper (48) .  ... 
doi:10.1021/bi0501840 pmid:16114870 pmcid:PMC2532597 fatcat:uvx76cawrjczzcmopp7pea3epe
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