New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process

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Title	New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process
Authors	Mohammad Amine ElGamacy¹, Raed Ahmed Shalaby¹, Ahmad Tawfik Elkodsh¹, Amr Fawzy Kamel¹, Mohamed Saad Abdullah Elsayed²*, Dalal Abd El Rahman Abou-El-Ella²
Affiliation	¹Faculty of pharmacy, Ain shams university; African union organization st, Abbasia, Cairo, Egypt; ²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University
Email	Mohamed.abdullah@pharm.asu.edu.eg; *Corresponding author
Phone	+202 29872434
Article Type	Hypothesis
Date	Received August 14, 2011; Accepted August 17, 2011; Published September 06, 2011
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.
Keywords	VEGFR-2; Docking; De novo design; Molecular dynamics
Citation	*ElGamacy et al.* Bioinformation 7(2): 52-58 (2011)
Edited by	P Kangueane
ISSN	0973-2063
Publisher	Biomedical Informatics
License	This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.