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

Abstract

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.

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…Detailed coverage of these other targets is outside the scope of this review,b ut their importance is evident. With the aim of helping to expand their corresponding investigation, we point out af ew interesting findings and reviews for more information: allostericm odulators of b-secretase (BACE), [235,236] allosteric modulators of acetylcholinesterase (AChE), [237][238][239][240] and allosteric modulators of s1r eceptors. [241] In general, form ost of the targets discussed herein, it is clear that the respective allostericinhibitors promote biological responses more selectively than orthosteric ligands.…”

“…Detailed coverage of these other targets is outside the scope of this review, but their importance is evident. With the aim of helping to expand their corresponding investigation, we point out a few interesting findings and reviews for more information: allosteric modulators of β‐secretase (BACE), allosteric modulators of acetylcholinesterase (AChE), and allosteric modulators of σ1 receptors …”

CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

“…In this case, a small molecule bound to a distant site can activate or inhibit the protein function or its interactions with other molecules as a result of structural changes that it induces at a distance [ 70 ]. However, for CTLA-4, such sites still have to be determined through either experimental or computational techniques [ 71 , 72 ].…”

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

“…After performing preliminary quality checks on the simulated protein dynamics data, conventional metrics such as the root mean square deviation (RMSD), residue root mean square fluctuation (RMSF), radius of gyration (Rg), and geometry calculations (distances and angles) can be performed to infer the stabilities (or instabilities) within protein-ligand complexes for the previously docked compounds [29,32,233,326,327]. Distal effects of interfacial residue variations within the renin-angiotensinogen complex were uncovered by Brown and colleagues using RMSF alongside BC [86].…”