Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations

Publisher： Bentham Science Publishers

E-ISSN： 1875-6697|11|2|124-136

ISSN： 1573-4099

Source： Current Computer - Aided Drug Design, Vol.11, Iss.2, 2015-09, pp. : 124-136

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Abstract

B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution ofvaline for glutamic acid at position 600 (lt;supgt;V600Elt;/supgt;B-Raf) is the most frequent. Treatment of these patients with B-Rafinhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have beenidentified and new potent and selective inhibitors are currently needed. In this work, five different type II inhibitors,which bind lt;supgt;V600Elt;/supgt;B-Raf in its DFG-out conformation, have been studied using molecular dynamics, free energycalculations and energy decomposition analysis. The ranking of calculated MM-PB/GBSA binding affinities is in goodagreement with the experimentally measured ones. The per-residue decomposition of ΔGlt;subgt;bindinglt;/subgt;, within the MM-GBSAapproach, has been used to identify the key residues governing the allosteric binding of the studied compounds to thelt;supgt;V600Elt;/supgt;B-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 ofDFG-out inhibitors to lt;supgt;V600Elt;/supgt;B-Raf, which can be used in a further step for rational design of a new class of B-Raf potentinhibitors.