Exploring Binding Mechanisms of VEGFR2 with Three Drugs Lenvatinib, Sorafenib and Sunitinib by Molecular Dynamics Simulation and Free Energy Calculation

Changes in protien flexibility caused by three different drugs (lenvatinib, sorafenib and sunitinib), and the detailed binding mechanism of them with VEGFR2 bound to the DFG‐in and DFG‐out state, were explored by multiple techniques. Impressively, out results suggested that lenvatinib could bind to both the DFG‐in and DFG‐out ststes of the kinase, while sorafenib and sunitinib could only bind the DFG‐out state of VEGFR2.

Abstract

Lenvatinib (LEN), sorafenib (SOR) and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG‐in and DFG‐out state, respectively. SUN binds to the DFG‐out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2‐drugs systems. Rank of calculated binding affinities is in accordance with the experimental data. The binding free energy calculation suggests that van der Waals interaction plays a vital role in the binding. Per‐residue free energy decomposition indicates that residues L840, V848, A866, E885, L889, V899, V916, F918, C919, L1035, C1045, D1046 and F1047 play an important role in the binding between VEGFR2 and LEN/SOR. While residues L840, V848, E917, F918, C919, G922, L1035 and F1047 contribute the major hydrophobic interaction for SUN binding to the receptor. Our results also reveal that residue E885/D1046 plays a vital role in binding via forming hydrogen bonds with drugs.

This article is protected by copyright. All rights reserved.

http://bit.ly/2DF7ovU