Journal
MOLECULAR PHARMACEUTICS
Volume 6, Issue 1, Pages 144-157Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp8001107
Keywords
B-RAF; molecular dynamics; MM-PBSA; docking; LBE; kinases
Funding
- Research Council for Technology and Production Sciences
- Program Commission on Nanoscience, Biotechnology and IT
- Bulgarian National Council for Scientific Research
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The B-RAF kinase plays an important role both in tumor induction and maintenance in several cancers. The molecular basis of the inactive B-RAF(WT) and B-RAF(V600E) inhibition and selectivity of a series of inhibitors was examined with a combination of molecular dynamics (MD), free energy MM-PBSA and local-binding energy (LBE) approaches. The conformational stability of the unbounded kinases and in particular the processes of the B-RAF(V600E) mutant activation were analyzed. A unique salt bridge network formed mainly by the catalytic residues was identified in the unbounded B-RAFs. The reorganization of this network and the restriction of the active segment flexibility upon ligand binding inhibit both B-RAF(WT) and B-RAF(V600E), thus appearing as an important factor for ligand selectivity. A significant correlation between the binding energies of the compounds in B-RAF(WT) and their inhibition effects on B-RAF(V600E) was revealed, which can explain the low mutant selectivity observed for numerous inhibitors. Our results suggest that the interactions between the activation segment and the alpha C-helix, as well as between the residues in the salt bridge network, are the major mechanism of the B-RAF(V600E) activation. Overall data revealed the important role of Lys601 for ligand activity, selectivity and protein stabilization, proposing an explanation of the observed strong kinase activation in the K601E mutated form.
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