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

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.

Optimizing the Calculation of Free Energy Differences in Nonequilibrium Work SQM/MM Switching Simulations

“… 3 − 5 Areas in which free energy simulations are used routinely include the computation of relative binding affinities in drug development 6 as well as the calculation of absolute binding affinities. 7 These methods do not only provide predictions of relative or absolute binding free energy differences but help to better understand the mechanisms of protein–ligand 8 , 9 as well as protein–protein interactions. 10 − 12 Whenever a chemical process of interest requires electronic scale details that molecular mechanics (MM) force field cannot provide, the tool of choice is hybrid quantum mechanical/molecular mechanical (QM/MM) calculations 13 − 16 for which the Nobel prize was awarded in 2013.…”

Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations

“…Meanwhile, the binding energies were decomposed into each residue, which were contributing to the binding energy ←1.00 kcal/mol, and were taken into consideration. 44 −CF 3 prefers Phe, Met, and Trp to −CH 3 (Figure 10). On the other hand, −CH 3 prefers Leu, Lys, and Glu to −CF 3 (Table S11 in the Supporting Information).…”

“…In 4ui3 and 3uod, etc., energy gains are mainly from solvation free energy (ΔΔ E gb = −7.60 and −12.93 kcal/mol, respectively). Meanwhile, the binding energies were decomposed into each residue, which were contributing to the binding energy ←1.00 kcal/mol, and were taken into consideration . −CF 3 prefers Phe, Met, and Trp to −CH 3 (Figure ).…”

An oleanolic acid derivative, K73‐03, inhibits pancreatic cancer cells proliferation in vitro and in vivo via blocking EGFR/Akt pathway

“…Consequently, flow cytometric analysis was performed to determine whether K73‐03 could induce PC cells death, which was associated with apoptosis. As shown in Figure 3 and 6, K73‐03 markedly increased in the Bax/Bcl‐2 ratio and caspase 3 activity both in vitro and in vivo, suggesting that the action of K73‐03 likely has been linked with intrinsic apoptosis, which is mediated via targeting of the mitochondria (Y. Wang et al, 2019; Yao et al, 2019). The cell cycle, featuring its various components and stages, and cell growth and division, forms a complex biological process (Martín‐Renedo et al, 2008; Tao et al, 2014).…”