Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach

Abstract

Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in silico analysis of interaction of vascular endothelial growth factor A (VEGFA), the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein-protein docking and molecular dynamics (MD) coupled to molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW) energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon) of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff) of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice.

VEGF-B Levels in the Vitreous of Diabetic and Non-Diabetic Patients with Ocular Diseases and Its Correlation with Structural Parameters

“…VEGF-A, VEGF-B, and PIGF (placental growth factor) bind to VEGFR-1 via D2 domains while VEGF-A binds to VEGFR-2 through the domains D2 and D3 [ 15 ]. Platania and colleagues studied the interactions of VEGF antagonists/VEGF-A complexes in silico and showed the differences in the interactions and affinities, although higher affinities alone do not always translate to better efficacy [ 16 ].…”

Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-Based Virtual Screening

“…Particle mesh Ewald method ( Linse and Linse, 2014 ) was used to calculate long-range electrostatic interactions. The binding free energy of inhibitors and PRMT5 was calculated by molecular mechanics generalized-born surface area (MM-GBSA) method ( Hou et al, 2010 ; Platania et al, 2015 ; Wang et al, 2017 ). A single trajectory and three time-frames protocols were adopted here.…”

Recent Developments and Applications of the MMPBSA Method

“…Studies of protein-protein interactions were also found for other diseases and disorders including serum paraoxonase 1 with high-density lipoprotein for antiatherosclerotic activity (Patra et al, 2014 ), vascular endothelial growth factor A with binding domains of anti-angiogenic agents for retinal neovascular degenerative diseases (Platania et al, 2015 ), angiotensin-converting enzyme with Angiotensin-II for hypertension (Guan et al, 2016 ), titin with T-cap/telethonin for dilated cardiomyopathy (Kumar D. T. et al, 2017 ), CC chemokine ligand 5 (CCL5) with human neutrophil peptide-1 (HNP1) for chronic inflammatory diseases (Wichapong et al, 2016 ), and ANKS6 with ANKS3 for polycystic kidney disease (Kan et al, 2016 ). In the study of CCL5 binding with human HNP1, Wichapong et al reported a correlation coefficient of r = 0.66 between experiment and MMPBSA results for different species of CCL5.…”