caa a22 4500 60551142X CHVBK 20210128100650.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s00894-015-2708-z doi (NATIONALLICENCE)springer-10.1007/s00894-015-2708-z Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase [Elektronische Daten] [Chunxia Gao, Morten Grøtli, Leif Eriksson] 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. Graphical Abstract Left Ribbon representation of DFG-out RET tyrosine kinase structure showing key residues of RET interacting with inhibitors. Right e-Pharmacophore hypothesis for RET-Abt-348 generated from the complex structure Springer-Verlag Berlin Heidelberg, 2015 RET nationallicence DFG-out inhibitors nationallicence Molecular dynamics simulation nationallicence MM-PB(GB)SA nationallicence e-pharmacophore nationallicence Gao Chunxia Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut Grøtli Morten Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut Eriksson Leif Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-12 1610-2940 21:7<1 2015 21 894 https://doi.org/10.1007/s00894-015-2708-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2708-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gao Chunxia Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut NATIONALLICENCE 700 1- Grøtli Morten Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut NATIONALLICENCE 700 1- Eriksson Leif Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-12 1610-2940 21:7<1 2015 21 894