Discovery of novel nonpeptide small-molecule NRP1 antagonists: Virtual screening, molecular simulation and structural modification

  • Bioorg Med Chem. 2020 Jan 1;28(1):115183. doi: 10.1016/j.bmc.2019.115183.
Kewen Peng  1 ,  Yu Li  1 ,  Ying Bai  1 ,  Teng Jiang  1 ,  Huiyong Sun  1 ,  Qihua Zhu  2 ,  Yungen Xu  3
Affiliations
  • 1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 31744780 DOI: 10.1016/j.bmc.2019.115183
Abstract

Multifaceted roles of vascular endothelial growth factor (VEGF)-neuropilin-1 (NRP1) interaction have been implicated in Cancer, but reports on small-molecule inhibitors of VEGF-NRP1 interaction are scarce. Herein, we describe the identification of 1, a novel nonpeptide small-molecule NRP1 antagonist with moderate activity via structure-based virtual screening. Ensemble docking and molecular dynamics (MD) simulations of 1 were carried out and an interesting binding model was obtained. We found that the "aromatic box" enclosed by Tyr297, Trp301 and Tyr353 of NRP1 is critical for NRP1-1 binding. Further structure modification of 1 based on the binding model derived from MD simulations resulted in the identification of 12a with significantly improved activity.

Keywords
Molecular dynamics; NRP1 antagonist; Neuropilin; VEGF; Virtual screening.
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