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http://hdl.handle.net/2445/132509
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DC Field | Value | Language |
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dc.contributor.author | Coronel, Luis | - |
dc.contributor.author | Granadino Roldán, José M. | - |
dc.contributor.author | Pinto, Marta | - |
dc.contributor.author | Santos Tomas, M. | - |
dc.contributor.author | Pujol Dilmé, M. Dolors | - |
dc.contributor.author | Rubio Martínez, Jaime | - |
dc.date.accessioned | 2019-04-29T15:39:01Z | - |
dc.date.available | 2019-04-29T15:39:01Z | - |
dc.date.issued | 2015 | - |
dc.identifier.issn | 1573-4099 | - |
dc.identifier.uri | http://hdl.handle.net/2445/132509 | - |
dc.description.abstract | B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution of valine for glutamic acid at position 600 (V600EB-Raf) is the most frequent. Treatment of these patients with B-Raf inhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have been identified and new potent and selective inhibitors are currently needed. In this work, five different type II inhibitors, which bind V600EB-Raf in its DFG-out conformation, have been studied using molecular dynamics, free energy calculations and energy decomposition analysis. The ranking of calculated MM-PB/GBSA binding affinities is in good agreement with the experimentally measured ones. The per-residue decomposition of ΔGbinding, within the MM-GBSA approach, has been used to identify the key residues governing the allosteric binding of the studied compounds to the V600EB-Raf protein kinase. Results indicate that although van der Waals interactions are key determinants for binding, hydrogen bonds also play an important role. This work also provides a better structural understanding of the binding of DFG-out inhibitors to V600EB-Raf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors. | - |
dc.format.extent | 13 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Bentham Science Publishers | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.2174/1573409911666150702100245 | - |
dc.relation.ispartof | Current Computer-Aided Drug Design, 2015, vol. 11, num. 2, p. 124-136 | - |
dc.relation.uri | https://doi.org/10.2174/1573409911666150702100245 | - |
dc.rights | (c) Bentham Science Publishers, 2015 | - |
dc.source | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) | - |
dc.subject.classification | Disseny de medicaments | - |
dc.subject.classification | Dinàmica molecular | - |
dc.subject.other | Drug design | - |
dc.subject.other | Molecular dynamics | - |
dc.title | Insight into the binding of DFG-out allosteric inhibitors to B-Raf Kinase using molecular dynamics and free energy calculations | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 655966 | - |
dc.date.updated | 2019-04-29T15:39:01Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Articles publicats en revistes (Ciència dels Materials i Química Física) |
Files in This Item:
File | Description | Size | Format | |
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655966.pdf | 995.38 kB | Adobe PDF | View/Open |
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