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

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 ?M) and butyrylcholinesterase (BuChE, IC₅₀ = 5.50 ± 0.007 ?M), respectively. Compound 3 was responsible for the formation of H-bond and ?-? 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.

SUBMITTER: Dighe SN

PROVIDER: S-EPMC7726787 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Dighe Satish N SN Tippana Mangapathiraju M van Akker Suzannah S Collet Trudi A TA

ACS omega 20201124 48

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 ...[more]

PMID: 33324805

Dataset Information

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

Publications

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

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