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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Peng K,Li Y,Bai Y,Jiang T,Sun H,Zhu Q,Xu Y

doi

10.1016/j.bmc.2019.115183

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

115183

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)31516-0

journal_volume

28

pub_type

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