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dc.contributor.author
Carlevaro, Carlos Manuel
dc.contributor.author
Martins da Silva, Joao Herminio
dc.contributor.author
Savino, Wilson
dc.contributor.author
Caffarena, Ernesto Raúl
dc.date.available
2017-09-05T13:15:18Z
dc.date.issued
2012-12
dc.identifier.citation
Carlevaro, Carlos Manuel; Martins da Silva, Joao Herminio ; Savino, Wilson; Caffarena, Ernesto Raúl; Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations; World Scientific; Journal Of Theoretical And Computational Chemistry; 12; 2; 12-2012; 1-16; 1250108
dc.identifier.issn
0219-6336
dc.identifier.uri
http://hdl.handle.net/11336/23640
dc.description.abstract
In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
World Scientific
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Integrin
dc.subject
Molecular Dynamics
dc.subject
Binding Mode
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Otras Ciencias Físicas
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Ciencias Físicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-09-01T17:44:22Z
dc.journal.volume
12
dc.journal.number
2
dc.journal.pagination
1-16; 1250108
dc.journal.pais
Singapur
dc.description.fil
Fil: Carlevaro, Carlos Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
dc.description.fil
Fil: Martins da Silva, Joao Herminio. Instituto Oswaldo Cruz; Brasil
dc.description.fil
Fil: Savino, Wilson. Instituto Oswaldo Cruz; Brasil
dc.description.fil
Fil: Caffarena, Ernesto Raúl. Instituto Oswaldo Cruz; Brasil
dc.journal.title
Journal Of Theoretical And Computational Chemistry
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1142/S0219633612501088
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.worldscientific.com/doi/abs/10.1142/S0219633612501088
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