Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation

Yaping Li; Yinglan Pu; Hui Liu; Li Zhang; Xingyong Liu; Yan Li; Zhili Zuo

doi:10.1007/s10822-018-0122-1

Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation

J Comput Aided Mol Des. 2018 Sep;32(9):901-915. doi: 10.1007/s10822-018-0122-1. Epub 2018 Sep 4.

Authors

Yaping Li^{1

2}, Yinglan Pu², Hui Liu², Li Zhang², Xingyong Liu², Yan Li³, Zhili Zuo^{4

5}

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
² School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, 643000, Sichuan, China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China. liyanb@mail.kib.ac.cn.
⁴ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China. zuozhili@mail.kib.ac.cn.
⁵ School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, 643000, Sichuan, China. zuozhili@mail.kib.ac.cn.

PMID: 30182144
DOI: 10.1007/s10822-018-0122-1

Abstract

Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC₅₀ value of 22.32 µM and a K_i value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor. Compound 8 was tested against A-549 tumor cell lines with IC₅₀ value of 17.8 µM. To investigate the intermolecular interaction of Wee1 and compound 8, further molecular dynamics simulations were performed. It indicates that the binding mode of compound 8 and reference ligand is similar. The active core scaffold of compound 8 could represent a promising lead compound for studying Wee1 and be used for further structural optimization to design more potent Wee1 inhibitors.

Keywords: Molecular docking; Molecular dynamics simulation; Pharmacophore model; Virtual screening; Wee1 inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry*
Cell Line, Tumor
Cell Survival / drug effects
Databases, Chemical
Humans
Hydrophobic and Hydrophilic Interactions
Kinetics
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / chemistry*
Protein Binding
Protein Conformation
Protein Kinase Inhibitors / chemistry*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry*
Quantitative Structure-Activity Relationship

Substances

Cell Cycle Proteins
Ligands
Nuclear Proteins
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
WEE1 protein, human