title: Discovery of novel inhibitors of vascular endothelial growth factor-A-Neuropilin-1 interaction by structure-based virtual screening.
abstract: Neuropilin-1 (NRP-1), one of the most important co-receptors of vascular endothelial growth factor-A (VEGF-A), increases its angiogenic action in several chronic diseases including cancer by increasing the activity of associated tyrosine kinase receptors, VEGFR1 and VEGFR2. Binding of VEGF-A to NRP-1 plays a critical role in pathological angiogenesis and tumor progression. Today, targeting this interaction is a validated approach to fight against angiogenesis-dependent diseases. Only anti-NRP-1 antibodies, peptide and peptidomimetic drug-candidates or hits have been developed thus far. In order to identify potent orally active small organic molecules various experimental and in silico approaches can be used. Here we report, novel promising small drug-like molecules disrupting the binding of VEGF-A₁₆₅ to NRP-1. We carried out structure-based virtual screening experiments using the ChemBridge compound collection on the VEGF-A₁₆₅ binding pocket of NRP-1. After docking and two rounds of similarity search computations, we identified 4 compounds that inhibit the biotinylated VEGF-A₁₆₅ binding to recombinant NRP-1 with Ki of about 10 μM. These compounds contain a common chlorobenzyloxy alkyloxy halogenobenzyl amine scaffold that can serve as a base for further development of new NRP-1 inhibitors.
authors: Université Paris 13, Sorbonne Paris Cité, EA4222, 74 rue Marcel Cachin, 93017 Bobigny cedex, France.
authors: Anna
authors: A
authors: Starzec
authors: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, 35 rue Helene Brion, 75013 Paris, France; INSERM, U973, F-75205 Paris, France. Electronic address: maria.miteva@univ-paris-diderot.fr.
authors: Maria A
authors: MA
authors: Miteva
authors: Université Paris 13, Sorbonne Paris Cité, CSPBAT, 74 rue Marcel Cachin, 93017 Bobigny cedex, France.
authors: Patrick
authors: P
authors: Ladam
authors: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, 35 rue Helene Brion, 75013 Paris, France; INSERM, U973, F-75205 Paris, France.
authors: Bruno O
authors: BO
authors: Villoutreix
authors: Université Paris 13, Sorbonne Paris Cité, EA4222, 74 rue Marcel Cachin, 93017 Bobigny cedex, France.
authors: Gérard Y
authors: GY
authors: Perret
mesh_terms: D000588:Amines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D062105:Molecular Docking Simulation; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000588:Amines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1
keywords: Angiogenesis; Neuropilin; Protein–protein interactions inhibitors; Structure-based virtual screening; VEGF