Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease

Fibrillar protein aggregates are characteristic of neurodegenerative diseases but represent difficult targets for ligand design, because limited structural information about the binding sites is available. Ligand-based virtual screening has been used to develop a computational method for the selection of new ligands for Aβ(1–42) fibrils, and five new ligands have been experimentally confirmed as nanomolar affinity binders. A database of ligands for Aβ(1–42) fibrils was assembled from the literature and used to train models for the prediction of dissociation constants based on chemical structure. The virtual screening pipeline consists of three steps: a molecular property filter based on charge, molecular weight, and logP; a machine learning model based on simple chemical descriptors; and machine learning models that use field points as a 3D description of shape and surface properties in the Forge software. The three-step pipeline was used to virtually screen 698 million compounds from the ZINC15 database. From the top 100 compounds with the highest predicted affinities, 46 compounds were experimentally investigated by using a thioflavin T fluorescence displacement assay. Five new Aβ(1–42) ligands with dissociation constants in the range 20–600 nM and novel structures were identified, demonstrating the power of this ligand-based approach for discovering new structurally unique, high-affinity amyloid ligands. The experimental hit rate using this virtual screening approach was 10.9%.

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“…We first compiled a data set of experimentally determined dissociation constants for ligand binding to Aβ(1–42) fibrils. − ...…”

Section: Resultsmentioning

confidence: 99%

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

2023

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“…In another article, Cui et al. reported a series of fluorescent probes with D‐π‐A architecture for the detection of Aβ plaques [62] . These probes were fluorescent turn‐on type and showed an increase in fluorescence intensity after incubation with Aβ 1–42 aggregates.…”

Section: Small Molecular Fluorescent Probes For Ad Associated Active ...mentioning

confidence: 99%

“…In another article, Cui et al reported a series of fluorescent probes with D-π-A architecture for the detection of Aβ plaques. [62] These probes were fluorescent turn-on type and showed an increase in fluorescence intensity after incubation with Aβ 1-42 aggregates. Among them, probes 20 a, 20 b and 20 c ( Pan group designed and synthesized two "D-A-D" conjugated fluorescent probes 21 a and 21 b (Figure 5) for selective imaging and inhibition of Aβ oligomer.…”

Section: Chemistry-a European Journalmentioning

confidence: 99%

Small Molecular Fluorescent Probes for Alzheimer's Disease Associated Active Species

Tang

Wang

Liu

et al. 2023

Chemistry A European J

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the main cause of dementia worldwide. As the pathogenesis of AD is quite complicated, there is continuous attention to AD‐associated active species, such as amyloid‐β plaques, neurofibrillary tangles, metal ions, reactive oxygen/nitrogen/sulphur species, cholinesterase, viscosity, formaldehyde and so on. To this end, a series of small molecular fluorescent probes for these active species have been explored for early diagnosis and even remedy of AD. Herein, we systematacially summarize the versatile fluorescent probes mainly in recent three years, including the relationship between the structure and properties as well as the targeted diagnosis and imaging application of all these fluorescent probes. Moreover, the challenges and perspectives of the AD‐related fluorescent probes are briefly explicated. We firmly expect this review may provide guidance for constructing new AD‐relevant fluorescent probes and promote the clinical study of AD.

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“…Probe 4b efficiently traced the Aβ plaques in vivo and washout quickly from the brain, reducing unspecific signals. 31 ■ CURCUMIN DERIVATIVES Curcumin derivatives were widely explored for their neuroprotection and therapeutic ability in neurodegenerative disorders and were found to have promising potential. 44 The derivatives consist of a diketone structure alongside a trans double bond.…”

Section: ■ Dicyanomethylene Derivativesmentioning

confidence: 99%

“…Fluorescent staining with Probe 4b identified the Aβ plaques in brain sections of both Tg mice and AD patients. Probe 4b efficiently traced the Aβ plaques in vivo and washout quickly from the brain, reducing unspecific signals …”

Section: Dicyanomethylene Derivativesmentioning

confidence: 99%

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-β Species in Alzheimer’s Disease

Bajad

Kumar

Singh

2023

ACS Chem. Neurosci.

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The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical regions of the brain of Alzheimer's disease (AD) patients is considered the foremost pathological hallmark of the disease. The early diagnosis of AD is paramount in order to effective management and treatment of the disease. Developing near-infrared fluorescence (NIRF) probes targeting Aβ species is a potential and attractive approach suitable for the early and timely diagnosis of AD. The advantages of the NIRF probes over other tools include real-time detection, higher sensitivity, resolution, comparatively inexpensive experimental setup, and noninvasive nature. Currently, enormous progress is being observed in the development of NIRF probes for the in vivo imaging of Aβ species. Several strategies, i.e., the classical push−pull approach, "turn-on" effect, aggregationinduced emission (AIE), and resonance energy transfer (RET), have been exploited for development. We have outlined and discussed the recently emerged NIRF probes with different design strategies targeting Aβ species for ex vivo and in vivo imaging. We believe that understanding the recent development enables the prospect of the rational design of probes and will pave the way for developing future novel probes for early diagnosis of AD.

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Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease

Cited by 11 publications

References 30 publications

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

Small Molecular Fluorescent Probes for Alzheimer's Disease Associated Active Species

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-β Species in Alzheimer’s Disease

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