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

Abstract

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.

A functional study of all 40 Caenorhabditis elegans insulin-like peptides

“…For instance, IGF-1 is one of the key molecules in cancer biology, however, little is known about the role of the E peptide. The E peptide is thought to have functional properties as the release from IGF-1 is thought to induce cellular proliferation in the human prostate cancer (39). The C peptide of proinsulin is important in the processing of mature insulin and may have biological activity as a report suggests that it binds to a G protein-coupled surface receptor and activates Ca 2ϩ -dependent intracellular signaling pathways (40).…”

Analysis of Biphenyl-Type Inhibitors Targeting the Eg5 α4/α6 Allosteric Pocket

“…The whole workflow of MD simulations was the same as that in those carried out in our previous studies. 28 , 29 , 39 A buffer distance of 10.0 Å was used to solvate the structures with TIP3P water in periodic boxes. To adjust the electroneutrality condition of the systems, 0.1 mol/L of Na + and Cl – ions were added.…”

“…The Eg5–PVZB1194 complex structure was retrieved from the protein databank (PDB ID: 3WPN). The default protein preparation wizard in Schrödinger was used to prepare and refine the structure in the same manner as in our previous studies. , First, the structure was checked to guarantee the chemical correctness. Hydrogens were added to the structure, and the side chains that were far from the binding pocket and not forming any salt bridges with other side chains were neutralized.…”

“…Four conventional 500 ns MD simulations were carried out on the Eg5–PVZB1194 complex structure and Eg5 protein structure only, in which the Amber 99 force field , and GROMACS software were used. The whole workflow of MD simulations was the same as that in those carried out in our previous studies. ,, A buffer distance of 10.0 Å was used to solvate the structures with TIP3P water in periodic boxes. To adjust the electroneutrality condition of the systems, 0.1 mol/L of Na + and Cl – ions were added.…”

Recent Developments and Applications of the MMPBSA Method

“…MMPBSA was widely applied in the development of anticancer compounds where kinases were identified as the most promising targets. Recent inhibitor design includes the epidermal growth factor receptor kinase domain (Li et al, 2015 ; Moonrin et al, 2015 ; Zhao et al, 2017 ), anaplastic lymphoma kinase (Kong et al, 2015 ), cyclin-dependent kinases (Li X. L. et al, 2014 ; Czelen, 2016 ; Dong et al, 2016a , b , 2017 ; Arba et al, 2017 ), extracellular signal-regulated kinase 2 (Chen, 2017 ), casein kinase 2 (Wang X. W. et al, 2014 ), sphingosine kinases (Fang et al, 2016 ), Src/Abl tyrosine kinases (Fong, 2015 ; Ma et al, 2015 ), RET tyrosine kinase (Gao et al, 2015 ), PRK1 (Slynko et al, 2014 ), Akt kinase (Lu et al, 2015 ), phosphatidylinositol 3 kinase (Bian et al, 2014 ), and Myt1 kinase (Wichapong et al, 2014 ). As an illustration of the method's performance, Slynko et al observed a correlation coefficient of 0.78 between the experimental pIC 50 of 26 PRK1 inhibitors and computational MMPBSA binding affinities.…”