Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies

You Zhou, Xin Lu, Chenxi Du, Yijun Liu, Yifan Wang, Kwon Ho Hong, Yao Chen, Haopeng Sun

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.

Original languageEnglish (US)
Article number127756
JournalBioorganic and Medicinal Chemistry Letters
Volume34
DOIs
StatePublished - Feb 15 2021

Bibliographical note

Funding Information:
This work was supported by Fundamental Research Funds for the Central Universities under Grant No. XDJK2019C103; National Natural Science Foundation of China [grant numbers 81803367, 81872728, and 81573281]; Basic Research and Frontier Exploration Project of Chongqing [grant number cstc2018jcyjAX0715]; Venture & Innovation Support Program for Chongqing Overseas Returnees.

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

  • Alzheimer's disease
  • Butyrylcholinesterase (BuChE)
  • Docking
  • Indoleamine 2,3-dioxygenase 1 (IDO1)
  • Multifunctional agents
  • Sertaconazole
  • Virtual screening

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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