Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation.

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.