Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations

Kongkai Zhu; Hongrui Tao; Jia-Li Song; Lu Jin; Yuanyuan Zhang; Jingqiu Liu; Zhifeng Chen; Cheng-Shi Jiang; Cheng Luo; Hua Zhang

doi:10.1016/j.bioorg.2018.08.021

Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations

Bioorg Chem. 2018 Dec:81:289-298. doi: 10.1016/j.bioorg.2018.08.021. Epub 2018 Aug 20.

Authors

Kongkai Zhu¹, Hongrui Tao², Jia-Li Song¹, Lu Jin³, Yuanyuan Zhang⁴, Jingqiu Liu⁴, Zhifeng Chen⁴, Cheng-Shi Jiang⁵, Cheng Luo⁶, Hua Zhang⁷

Affiliations

¹ School of Biological Science and Technology, University of Jinan, Jinan 250022, PR China.
² School of Biological Science and Technology, University of Jinan, Jinan 250022, PR China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Germany.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁵ School of Biological Science and Technology, University of Jinan, Jinan 250022, PR China. Electronic address: jiangchengshi-20@163.com.
⁶ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: cluo@simm.ac.cn.
⁷ School of Biological Science and Technology, University of Jinan, Jinan 250022, PR China. Electronic address: bio_zhangh@ujn.edu.cn.

PMID: 30172110
DOI: 10.1016/j.bioorg.2018.08.021

Abstract

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC₅₀ values against PRMT5 at enzymatic level were ranging from 0.77 to 23 μM. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC₅₀ values lower than 10 μM and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation.

Keywords: Arginine methylation; Molecular docking; Molecular dynamics simulation; PRMT5 inhibitor; Virtual screening.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzylidene Compounds / chemistry
Benzylidene Compounds / pharmacology*
Binding Sites
Cell Line, Tumor
Databases, Chemical*
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
Protein-Arginine N-Methyltransferases / chemistry
Structure-Activity Relationship
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antineoplastic Agents
Benzylidene Compounds
Thiazoles
PRMT5 protein, human
Protein-Arginine N-Methyltransferases