Identification of new allosteric sites and modulators of AChE through computational and experimental tools

Journal of Enzyme Inhibition and Medicinal Chemistry

Carlos Requena¹  Víctor Sebastián-Pérez¹  Ana Martinez¹  Carlos Roca¹  Nuria E. Campillo¹  Tom L. Blundell²  Sony Malhotra²  Chris Radoux³  Concepción Pérez⁴  Juan Antonio Páez⁴ 

[1]Centro de Investigaciones Biológicas (CIB-CSIC), C/Ramiro de Maeztu, Madrid, Spain

[2]Department of Biochemistry, University of Cambridge, Cambridge, UK

[3]Department of Biochemistry, University of Cambridge, Cambridge, UK

[4]Cambridge Crystallographic Data Centre, Cambridge, UK

[5]Instituto de Química Médica (IQM-CSIC), C/Juan de la Cierva, Madrid, Spai

关键词: AChE;    allosteric sites;    Alzheimer diseases;    molecular dynamics;    allosteric inhibitors;   

DOI  :  10.1080/14756366.2018.1476502

来源: publisher

【 摘 要 】

Allosteric sites on proteins are targeted for designing more selective inhibitors of enzyme activity and to discover new functions. Acetylcholinesterase (AChE), which is most widely known for the hydrolysis of the neurotransmitter acetylcholine, has a peripheral allosteric subsite responsible for amyloidosis in Alzheimer’s disease through interaction with amyloid β-peptide. However, AChE plays other non-hydrolytic functions. Here, we identify and characterise using computational tools two new allosteric sites in AChE, which have allowed us to identify allosteric inhibitors by virtual screening guided by structure-based and fragment hotspot strategies. The identified compounds were also screened for in vitro inhibition of AChE and three were observed to be active. Further experimental (kinetic) and computational (molecular dynamics) studies have been performed to verify the allosteric activity. These new compounds may be valuable pharmacological tools in the study of non-cholinergic functions of AChE.

【 授权许可】

CC BY