title: Molecular modelling, synthesis and biological evaluation of peptide inhibitors as anti-angiogenic agent targeting neuropilin-1 for anticancer application.
abstract: Vascular endothelial growth factor (VEGF) and its co-receptor neuropilin-1 (NRP-1) are important targets of many pro-angiogenic factors. In this study, nine peptides were synthesized and evaluated for their molecular interaction with NRP-1 and compared to our previous peptide ATWLPPR. Docking study showed that the investigated peptides shared the same binding region as shown by tuftsin known to bind selectively to NRP-1. Four pentapeptides (DKPPR, DKPRR, TKPPR and TKPRR) and a hexapeptide CDKPRR demonstrated good inhibitory activity against NRP-1. In contrast, peptides having arginine residue at sites other than the C-terminus exhibited low activity towards NRP-1 and this is confirmed by their inability to displace the VEGF165binding to NRP-1. Docking study also revealed that replacement of carboxyl to amide group at the C-terminal arginine of the peptide did not affect significantly the binding interaction to NRP-1. However, the molecular affinity study showed that these peptides have marked reduction in the activity against NRP-1. Pentapeptides having C-terminal arginine showed strong interaction and good inhibitory activity with NRP thus may be a good template for anti-angiogenic targeting agent.
authors.affiliation: a School of Pharmaceutical Sciences , Universiti Sains Malaysia , 11800 Penang , Malaysia.|b LCPM, UMR-CNRS 7375, Université de Lorraine, ENSIC , 1 Rue Grandville, F-54000 Nancy , France.
authors.forename: Ezatul E
authors.initials: EE
authors.lastname: Kamarulzaman
authors.affiliation: b LCPM, UMR-CNRS 7375, Université de Lorraine, ENSIC , 1 Rue Grandville, F-54000 Nancy , France.
authors.forename: Régis
authors.initials: R
authors.lastname: Vanderesse
authors.affiliation: b LCPM, UMR-CNRS 7375, Université de Lorraine, ENSIC , 1 Rue Grandville, F-54000 Nancy , France.
authors.forename: Amirah M
authors.initials: AM
authors.lastname: Gazzali
authors.affiliation: c CRAN, UMR-CNRS 7039 , Campus Science, BP 70239, F-54506 Vandœuvre-lès-Nancy , France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Barberi-Heyob
authors.affiliation: c CRAN, UMR-CNRS 7039 , Campus Science, BP 70239, F-54506 Vandœuvre-lès-Nancy , France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Boura
authors.affiliation: d LRGP , UMR-CNRS 7274, Université de Lorraine, ENSIC , 1 Rue Grandville, F-54000 Nancy , France.
authors.forename: Céline
authors.initials: C
authors.lastname: Frochot
authors.affiliation: e Chemical Sciences Programme , School of Distance Education, Universiti Sains Malaysia , 11800 Penang , Malaysia.
authors.forename: Omar
authors.initials: O
authors.lastname: Shawkataly
authors.affiliation: b LCPM, UMR-CNRS 7375, Université de Lorraine, ENSIC , 1 Rue Grandville, F-54000 Nancy , France.
authors.forename: André
authors.initials: A
authors.lastname: Aubry
authors.affiliation: a School of Pharmaceutical Sciences , Universiti Sains Malaysia , 11800 Penang , Malaysia.|f Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation , Jalan Bukit Gambir, 11800 Penang , Malaysia.
authors.forename: Habibah A
authors.initials: HA
authors.lastname: Wahab
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008024:Ligands; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1
keywords: ELISA; VEGFR; angiogenesis; docking study; in vitro binding; molecular modelling; neuropilin-1; synthetic peptides