Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

Satish N Dighe; Mangapathiraju Tippana; Suzannah van Akker; Trudi A Collet

doi:10.1021/acsomega.0c03848

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

ACS Omega. 2020 Nov 24;5(48):30971-30979. doi: 10.1021/acsomega.0c03848. eCollection 2020 Dec 8.

Authors

Satish N Dighe¹, Mangapathiraju Tippana¹, Suzannah van Akker¹, Trudi A Collet¹

Affiliation

¹ Institute of Health & Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia.

Abstract

Cholinesterases (ChE) are well-known drug targets for the treatment of Alzheimer's disease (AD). In continuation of work to develop novel cholinesterase inhibitors, we utilized a structure-based scaffold repurposing approach and discovered six novel ChE inhibitors from our recently developed DNA gyrase inhibitor library. Among the identified hits, two compounds (denoted 3 and 18) were found to be the most potent inhibitor of acetylcholinesterase (AChE, IC₅₀ = 6.10 ± 1.01 μM) and butyrylcholinesterase (BuChE, IC₅₀ = 5.50 ± 0.007 μM), respectively. Compound 3 was responsible for the formation of H-bond and π-π stacking interactions within the active site of AChE. In contrast, compound 18 was well fitted in the choline-binding pocket and catalytic site of BuChE. Results obtained from in vitro cytotoxicity assays and in silico derived physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties indicate that repurposed scaffold 3 and 18 could be potential drug candidates for further development as novel ChE inhibitors.