Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease

Hiroyuki Konno; Masaki Wakabayashi; Daiki Takanuma; Yota Saito; Kenichi Akaji

doi:10.1016/j.bmc.2016.01.052

Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease

Bioorg Med Chem. 2016 Mar 15;24(6):1241-54. doi: 10.1016/j.bmc.2016.01.052. Epub 2016 Jan 29.

Authors

Hiroyuki Konno¹, Masaki Wakabayashi², Daiki Takanuma², Yota Saito², Kenichi Akaji³

Affiliations

¹ Department of Biological Engineering, Graduate School of Science and Technology, Yamagata University, Yonezawa, Yamagata 992-8510, Japan. Electronic address: konno@yz.yamagata-u.ac.jp.
² Department of Biological Engineering, Graduate School of Science and Technology, Yamagata University, Yonezawa, Yamagata 992-8510, Japan.
³ Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: akaji@mb.kyoto-phu.ac.jp.

Abstract

Synthesis of serine derivatives having the essential functional groups for the inhibitor of SARS 3CL protease and evaluation of their inhibitory activities using SARS 3CL R188I mutant protease are described. The lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and Bai's cinnamoly inhibitor, and additionally performed with simulation on GOLD softwear. Structure activity relationship studies of the candidate compounds were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant protease. These inhibitors showed protease selectivity and no cytotoxicity.

Keywords: Cathepsin B; Cytotoxicity; Docking simulation; SARS 3CL protease; SARS CoV; Serine derivative.

Publication types

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

MeSH terms

Cell Death / drug effects
Coronavirus 3C Proteases
Cysteine Endopeptidases / metabolism
Dose-Response Relationship, Drug
Drug Design*
HeLa Cells
Humans
Molecular Docking Simulation
Molecular Structure
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Serine / analogs & derivatives*
Serine / chemical synthesis
Serine / pharmacology
Severe acute respiratory syndrome-related coronavirus / enzymology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Viral Proteins / antagonists & inhibitors*
Viral Proteins / metabolism

Substances

Protease Inhibitors
Small Molecule Libraries
Viral Proteins
Serine
Cysteine Endopeptidases
Coronavirus 3C Proteases