Article ; Online: Acetylcholinesterase: A Versatile Template to Coin Potent Modulators of Multiple Therapeutic Targets.
2024
Abstract: ConspectusThe enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic ... ...
| Abstract | ConspectusThe enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic deficit, prominently Alzheimer's disease (AD). Working at a rate near the diffusion limit, it is considered one of nature's most efficient enzymes. This is particularly meritorious considering that its catalytic site is buried at the bottom of a 20-Å-deep cavity, which is preceded by a bottleneck with a diameter shorter than that of the trimethylammonium group of ACh, which has to transit through it. Not only the particular architecture and amino acid composition of its active site gorge enable AChE to largely overcome this potential drawback, but it also offers plenty of possibilities for the design of novel inhibitor drug candidates.In this Account, we summarize our different approaches to colonize the vast territory of the AChE gorge in the pursuit of increased occupancy and hence of inhibitors with increased affinity. We pioneered the use of molecular hybridization to design inhibitors with extended binding at the CAS, reaching affinities among the highest reported so far. Further application of molecular hybridization to grow CAS extended binders by attaching a PAS-binding moiety through suitable linkers led to multisite inhibitors that span the whole length of the gorge, reaching the PAS and even interacting with midgorge residues. We show that multisite AChE inhibitors can also be successfully designed the other way around, by starting with an optimized PAS binder and then colonizing the gorge and CAS. Molecular hybridization from a multicomponent reaction-derived PAS binder afforded a single-digit picomolar multisite AChE inhibitor with more than 1.5 million-fold increased potency relative to the initial hit. This illustrates the powerful alliance between molecular hybridization and gorge occupancy for designing potent AChE inhibitors.Beyond AChE, we show that the stereoelectronic requirements imposed by the AChE gorge for multisite binding have a templating effect that leads to compounds that are active in other key biological targets in AD and other neurological and non-neurological diseases, such as BACE-1 and the aggregation of amyloidogenic proteins (β-amyloid, tau, α-synuclein, prion protein, transthyretin, and human islet amyloid polypeptide). The use of known pharmacophores for other targets as the PAS-binding motif enables the rational design of multitarget agents with multisite binding within AChE and activity against a variety of targets or pathological events, such as oxidative stress and the neuroinflammation-modulating enzyme soluble epoxide hydrolase, among others.We hope that our results can contribute to the development of drug candidates that can modify the course of neurodegeneration and may inspire future works that exploit the power of molecular hybridization in other proteins featuring large cavities. |
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| Language | English |
| Publishing date | 2024-02-09 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1483291-4 |
| ISSN | 1520-4898 ; 0001-4842 |
| ISSN (online) | 1520-4898 |
| ISSN | 0001-4842 |
| DOI | 10.1021/acs.accounts.3c00617 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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