Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring

You Zhou; Yanyu Hu; Xin Lu; Hongyu Yang; Qihang Li; Chenxi Du; Yao Chen; Kwon Ho Hong; Haopeng Sun

doi:10.1177/1559325820938526

Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring

Dose Response. 2020 Jun 29;18(2):1559325820938526. doi: 10.1177/1559325820938526. eCollection 2020 Apr-Jun.

Authors

You Zhou¹, Yanyu Hu², Xin Lu², Hongyu Yang², Qihang Li², Chenxi Du², Yao Chen³, Kwon Ho Hong⁴, Haopeng Sun²

Affiliations

¹ College of Biotechnology, Southwest University, Chongqing, China.
² School of Pharmacy, China Pharmaceutical University, Nanjing, China.
³ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Abstract

Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC₅₀ = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure-activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.

Keywords: Alzheimer disease; MM-GBSA rescoring; preliminary structure–activity relationship study; selective butyrylcholinesterase inhibitors; structure-based virtual screening.