Homology Modeling and Docking Evaluation of Aminergic G Protein-Coupled Receptors

2010 ◽  
Vol 50 (4) ◽  
pp. 626-637 ◽  
Author(s):  
Fiona M. McRobb ◽  
Ben Capuano ◽  
Ian T. Crosby ◽  
David K. Chalmers ◽  
Elizabeth Yuriev
Keyword(s):  
Homology Modeling ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Modern Homology Modeling of G-Protein Coupled Receptors: Which Structural Template to Use?

2009 ◽  
Vol 52 (16) ◽  
pp. 5207-5216 ◽  
Author(s):  
Juan Carlos Mobarec ◽  
Roberto Sanchez ◽  
Marta Filizola
Keyword(s):  
Homology Modeling ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structural Template ◽  
G Protein Coupled

scholarly journals On Template Selection for Homology Modeling of G-Protein Coupled Receptors

2009 ◽  
Vol 96 (3) ◽  
pp. 653a
Author(s):  
Juan Carlos Mobarec ◽  
Roberto Sanchez ◽  
Marta Filizola
Keyword(s):  
Homology Modeling ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Template Selection ◽  
Selection For ◽  
G Protein Coupled

Efficiency of Homology Modeling assisted Molecular Docking in G-protein coupled receptors

2020 ◽  
Vol 20 ◽  
Author(s):  
Shome S. Bhunia ◽  
Anil K. Saxena
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Homology Modeling ◽  
Crystal Structures ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Protein Crystal ◽  
Protein Crystal Structure ◽  
Rational Drug ◽  
G Protein Coupled

Background: Molecular docking is in regular practice to assess ligand affinity on a target protein crystal structure. In absence of protein crystal structure, the homology modeling or comparative modeling is the best alternative to elucidate the relationship details between a ligand and protein at the molecular level. The development of accurate homology modeling (HM) and its integration with molecular docking (MD) is essential for successful, rational drug discovery. Objective: The G-protein coupled receptors (GPCRs) are attractive therapeutic targets due to their immense role in human pharmacology. The GPCRs are membrane bound proteins with complex constitution and the understanding of their activation and inactivation mechanisms is quite challenging. Over the past decade there has been a rapid expansion in the number of solved G-protein-coupled receptor (GPCR) crystal structures however majority of the GPCR structures remain unsolved. In this context HM guided MD has been widely used for structure-based drug design (SBDD) of GPCRs. Methods: The focus of this review is on the recent (i) developments on HM supported GPCR drug discovery in absence of GPCR crystal structures (ii) application of HM in understanding the ligand interactions at the binding site, virtual screening, determining receptor sub type selectivity and receptor behaviour in comparison with GPCR crystal structures . Results: The HM in GPCRs has been extremely challenging due to the scarcity in template structures. In such a scenario it is difficult to get accurate HM that can facilitate understanding of the ligand-receptor interactions. This problem has been alleviated to some extent by developing refined HM based on incorporating active /inactive ligand information and inducing protein flexibility. In some cases HM proteins were found to outscore crystal structures also. Conclusion: The developments in HM have been highly operative to gain insights about the ligand interaction at the binding site and receptor functioning at molecular level. Thus HM guided molecular docking may be useful for rational drug discovery for the GPCRs mediated diseases.

scholarly journals RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta

2019 ◽  
Author(s):  
Brian Joseph Bender ◽  
Brennica Marlow ◽  
Jens Meiler
Keyword(s):  
Protein Structure ◽  
Drug Development ◽  
Homology Modeling ◽  
Computational Modeling ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Extracellular Loops ◽  
Model Database ◽  
G Protein Coupled ◽  
Multiple Template

AbstractG-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies. However, to date, only about 10% of druggable GPCRs have had their structures characterized at atomic resolution. Further, because of the flexibility of GPCRs, alternative conformations remain to be modeled, even after an experimental structure is available. Thus, computational modeling of GPCRs is a crucial component for understanding biological function and to aid development of new therapeutics. Previous single- and multi-template homology modeling protocols in Rosetta often generated non-native-like conformations of transmembrane α-helices and/or extracellular loops. Here we present a new Rosetta protocol for modeling GPCRs that is improved in two critical ways: Firstly, it uses a blended sequence- and structure-based alignment that now accounts for structure conservation in extracellular loops. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target GPCR can be used expanding the conformational space sampled in a meaningful way. This new method allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org.Author SummaryStructure-based drug discovery is among the new technologies driving the development of next generation therapeutics. Inherent to this process is the availability of a protein structure for virtual screening. The most heavily drugged protein family, G-protein coupled receptors (GPCRs), however suffers from a lack of experimental structures that could hinder drug development. Technical challenges prevent the determination of every protein structure, so we turn to computational modeling to predict the structures of the remaining proteins. Again, traditional techniques fail due to the high divergence of this family. Here, we build on available methods specifically for the challenge of modeling GPCRs. This new method outperforms other methods and allows for the ability to accurately model nearly 90% of the entire GPCR family. We therefore generate a model database of all GPCRs (www.rosettagpcr.org) for use in future drug development.

Impact of Helix Irregularities on Sequence Alignment and Homology Modeling of G Protein-Coupled Receptors

ChemBioChem ◽  
2012 ◽  
Vol 13 (10) ◽  
pp. 1393-1399 ◽  
Author(s):  
Angel Gonzalez ◽  
Arnau Cordomí ◽  
Gianluigi Caltabiano ◽  
Leonardo Pardo
Keyword(s):  
Homology Modeling ◽  
G Protein ◽  
Sequence Alignment ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled
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