Abstract
We are reporting the discovery of small molecule inhibitors for vascular endothelial growth factor receptor type 2 (VEGFR-2) extracellular domain. The VEGFR-2 extracellular domain is responsible for the homo-dimerization process, which has been recently reported as a main step in VEGFR signal transduction cascade. This cascade is essential for the vascularization and survival of most types of cancers. Two main design strategies were used; Molecular docking-based Virtual Screening and Fragment Based Design (FBD). A virtual library of drug like compounds was screened using a cascade of docking techniques in order to discover an inhibitor that binds to this new binding site. Rapid docking methodology was used first to filter the large number of compounds followed by more accurate and slow ones. Fragment based molecular design was adopted afterwards due to unsatisfactory results of screening process. Screening and design process resulted in a group of inhibitors with superior binding energies exceeding that of the natural substrate. Molecular dynamics simulation was used to test the stability of binding of these inhibitors and finally the drug ability of these compounds was assisted using Lipinski rule of five. By this way the designed compounds have shown to possess high pharmacologic potential as novel anticancer agents.
Highlights
Neo-angiogenesis has a crucial role in the progression and survival of most types of cancer beside some other proliferative diseases [1]
Scoring and Energetics: The ligand-receptor complexes of selected clustered poses from each flexibly docked ligand, as well as the designed ligands were further subject to a minimization process using the 'Minimization' protocol in Discovery Studio (DS) 2.5 through the 'Smart Minimizer' – steepest-descent followed by conjugate gradient method – until potential energy root mean square (RMS) gradient was less than 0.05 kcal/mol/Å, with generalized born simple switching implicit solvation at salt concentration of 0.145 M to better mimic physiological conditions [20]
The detailed investigation conducted by Yang et al, [11] concluded the critical role of the dimerization process of D7 through the homotypic contacts in ligand-induced (VEGF-A) autophosphorylation of vascular endothelial growth factor receptor type 2 (VEGFR-2) and that latter's eventual activation
Summary
Neo-angiogenesis has a crucial role in the progression and survival of most types of cancer beside some other proliferative diseases [1]. Materials and Methodology: The 3D X-ray crystal structure of monomeric and homodimeric forms of membrane-proximal Ig-like domain of the ectodomain (D7) of VEGFR-2 [PDB ID: 3KVQ] was exploited as target for vitrual High-throughput screening (v-HTS) and fragment-based design (FBD) Both the proteins were prepared, undergone rigid and flexible docking, energetically probed, and subjected to molecular dynamics (MD) simulations. Scoring and Energetics: The ligand-receptor complexes of selected clustered poses from each flexibly docked ligand, as well as the designed ligands were further subject to a minimization process using the 'Minimization' protocol in DS 2.5 through the 'Smart Minimizer' – steepest-descent followed by conjugate gradient method – until potential energy RMS gradient was less than 0.05 kcal/mol/Å, with generalized born simple switching implicit solvation at salt concentration of 0.145 M to better mimic physiological conditions [20]. FBD is capable of generating more robust solutions provided chemical compatibility and synthetic feasibility are addressed
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