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

• 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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

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

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