Identification of SENP1 inhibitors through in silico screening and rational drug design

Yaxue Zhao; Zhongli Wang; Jianchen Zhang; Huchen Zhou

doi:10.1016/j.ejmech.2016.06.018

Identification of SENP1 inhibitors through in silico screening and rational drug design

Eur J Med Chem. 2016 Oct 21:122:178-184. doi: 10.1016/j.ejmech.2016.06.018. Epub 2016 Jun 14.

Authors

Yaxue Zhao¹, Zhongli Wang¹, Jianchen Zhang¹, Huchen Zhou²

Affiliations

¹ State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
² State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China. Electronic address: hczhou@sjtu.edu.cn.

PMID: 27344494
DOI: 10.1016/j.ejmech.2016.06.018

Abstract

The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 μM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed.

Keywords: Cancer; In silico screening; Rational design; SENP1 inhibitor.

MeSH terms

Computer Simulation*
Drug Design*
Drug Evaluation, Preclinical
Endopeptidases / metabolism*
Inhibitory Concentration 50
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Protease Inhibitors
Endopeptidases