Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/132509
Title: | Insight into the binding of DFG-out allosteric inhibitors to B-Raf Kinase using molecular dynamics and free energy calculations |
Author: | Coronel, Luis Granadino Roldán, José M. Pinto, Marta Santos Tomas, M. Pujol Dilmé, M. Dolors Rubio Martínez, Jaime |
Keywords: | Disseny de medicaments Dinàmica molecular Drug design Molecular dynamics |
Issue Date: | 2015 |
Publisher: | Bentham Science Publishers |
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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.2174/1573409911666150702100245 |
It is part of: | Current Computer-Aided Drug Design, 2015, vol. 11, num. 2, p. 124-136 |
URI: | http://hdl.handle.net/2445/132509 |
Related resource: | https://doi.org/10.2174/1573409911666150702100245 |
ISSN: | 1573-4099 |
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 | |
---|---|---|---|---|
655966.pdf | 995.38 kB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.