title: Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations.
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 ((V600E)B-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 (V600E)B-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 (V600E)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 of DFG-out inhibitors to (V600E)B-Raf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors.
authors.forename: Luis
authors.initials: L
authors.lastname: Coronel
authors.forename: Jose M
authors.initials: JM
authors.lastname: Granadino-Roldán
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.forename: Maria S
authors.initials: MS
authors.lastname: Tomas
authors.forename: Maria D
authors.initials: MD
authors.lastname: Pujol
authors.affiliation: Department of Physical Chemistry, University of Barcelona and the Institut de Recerca en Quimica Teorica i Computacional (IQTCUB), Barcelona, Spain. jaime.rubio@ub.edu.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D017076:Computer-Aided Design; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf