Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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

Author(s): Luis Coronel, Jose M. Granadino-Roldán, Marta Pinto, Maria S. Tomas, Maria D. Pujol, Jaime Rubio-Martinez.

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.

Keywords: B-Raf, DFG-out, drug design, MM-PB/GBSA, molecular dynamics, type II inhibitors.

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Article Details

VOLUME: 11
ISSUE: 2
Year: 2015
Page: [124 - 136]
Pages: 13
DOI: 10.2174/1573409911666150702100245
Price: $58