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.
Highlights
Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis through activation of specific receptors (VEGFR)
Notice that VEGFR1d2_R2d3/vascular endothelial growth factor A (VEGFA) was stabilized by electrostatic interaction energy compared to Fragment antigen-binding (Fab)-bevacizumab/VEGFA and ranibizumab/VEGFA complexes, which were rather characterized by stabilizing desolvation and Van der Waals (VdW) energy terms
We have limited our study to interaction between VEGFA and binding domains of the above mentioned anti-VEGF drugs, excluding the fragment crystallizable region (Fc) fragment of aflibercept and bevacizumab, because the Fc fragment does not seem to influence the pharmacodynamic properties of these drugs (Stewart, 2014b)
Summary
Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis through activation of specific receptors (VEGFR). Anti-angiogenic agents have been used to treat ocular pathological conditions such as age-related macular degeneration (AMD) and diabetic macular edema (DME) (Holz et al, 2014; Stewart, 2014a). Bevacizumab is a humanized monoclonal antibody, ranibizumab is the mutated Fab (Fragment antigen-binding) of the monoclonal antibody (Ab) originating bevacizumab and aflibercept is a fusion protein that works as decoy VEGF receptor (Figure 1). Aflibercept, known as VEGF-trap, is a decoy receptor where two binding domains, the domain 2 (d2) of VEGFR1 and the domain 3 (d3) of VEGFR2 (from N-terminus to C-terminus of primary sequence) are connected to the fragment crystallizable region (Fc) of human immunoglobulin (Ig) (Holash et al, 2002). Throughout the text the binding domain of aflibercept is named “VEGFR1d2_R2d3.”
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