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Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase

Journal article
Authors Chunxia Gao
Morten Grøtli
Leif A Eriksson
Published in Journal of Molecular Modeling
Volume 21
Issue 7
Pages Article Number: 167
ISSN 1610-2940
Publication year 2015
Published at Department of Chemistry and Molecular Biology
Pages Article Number: 167
Language en
Keywords RET, DFG-out inhibitors, Molecular dynamics simulation, MM-PB(GB)SA, e-pharmacophore, MEDULLARY-THYROID CANCER, PARTICLE MESH EWALD, MOLECULAR-MECHANICS, FREE-ENERGIES, BINDING-SITE, FORCE-FIELD, MODEL, CONFORMATIONS, DYNAMICS, DESIGN, Biochemistry & Molecular Biology, Biophysics, Chemistry,, Multidisciplinary, Computer Science, Interdisciplinary Applications, ATES OF AMERICA, V109, P18281, WAR MJS, 1985, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, V107, P3902
Subject categories Biochemistry and Molecular Biology


RET (rearranged during transfection) tyrosine kinase is a promising target for several human cancers. Abt-348, Birb-796, Motesanib and Sorafenib are DFG-out multi-kinase inhibitors that have been reported to inhibit RET activity with good IC50 values. Although the DFG-out conformation has attracted great interest in the design of type II inhibitors, the structural requirements for binding to the RET DFG-out conformation remains unclear. Herein, the DFG-out conformation of RET was determined by homology modelling, the four inhibitors were docked, and the binding modes investigated by molecular dynamics simulation. Binding free energies were calculated using the molecular mechanics/Poisson-Bolzmann surface area (MM/PBSA) method. The trends in predicted binding free affinities correlated well with experimental data and were used to explain the activity difference of the studied inhibitors. Per-residue energy decomposition analyses provided further information on specific interaction properties. Finally, we also conducted a detailed e-pharmacophore modelling of the different RET-inhibitor complexes, explaining the common and specific pharmacophore features of the different complexes. The results reported herein will be useful in future rational design of novel DFG-out RET inhibitors.

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