Versatile Dicyanomethylene-Based Fluorescent Probes for the Detection of β-Amyloid in Alzheimer’s Disease: A Theoretical Perspective

Abstract

Motivated by the growing demand for target chemosensors designed with diagnostic or therapeutic capability for fibrils related to amyloidosis diseases, we investigated in the present work the response mechanism of dicyanomethylene-based fluorescent probes for amyloid fibril using a combined approach, including molecular docking, quantum mechanics/molecular mechanics (QM/MM), and the quantum chemical method. Various binding modes for the probes in β-amyloid (Aβ) are discussed, and the fibril environment-induced molecular optical changes at the most stable site are compared to the fibril-free situation in aqueous environments. The results reveal that the fluorescence enhancement for the probes in Aβ observed experimentally is an average consequence over multiple binding sites. In particular, the conformational difference, including conjugation length and donor effect, significantly contributes to the optical property of the studied probes both in water and fibril. To further estimate the transition nature of the molecular photoabsorption and photoemission processes, the hole-electron distribution and the structural variation on the first excited state of the probes are investigated in detail. On the basis of the calculations, structure–property relationships for the studied chemosensors are established. Our computational approach with the ability to elucidate the available experimental results can be used for designing novel molecular probes with applications to Aβ imaging and the early diagnosis of Alzheimer’s disease.

Molecular Design of Magnetic Resonance Imaging Agents Binding to Amyloid Deposits

“…Dicyanomethylene derivatives [ 30 , 141 , 142 ]. A well-known representative is the PET probe FDDNP ( Figure 23 a) [ 143 ], used for research purposes.…”

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

“…Experimentally, dicyanomethylene has shown potential for selective binding affinity to Aβ aggregates, along with excellent fluorescence enhancement. 30 Cui et al reported different NIRF probes containing the dicyanomethylene group for targeting Aβ deposits. In the initial series, N,N′-dimethylamino group attached to the benzene ring was chosen as the electron donor and the dicyanomethylene group as the electron acceptor, interconnected by conjugated double bonds (DNIRs).…”

“…The report proposed a comprehensive consideration of binding affinity, where the efficiency of the dicyanomethylene-based fluorescent probe for Aβ species could be improved through the combined πconjugate extension and adjusting the ability of electron donating/accepting groups of the fluorophore. 30 The NIRF probe was also reported with a selective turn-on fluorescence effect when it bound to the target, which may improve the detection of Aβ species and enable in vivo molecular imaging quantitatively. The fluorescence tends to emit, selectively turned on, by the rotatable donor−acceptor bond when the intramolecular rotational relaxation about the donor−acceptor bond is constrained.…”

“…Since then, the dicyanomethylene moiety has been used as an electron acceptor for the construction of donor–acceptor architecture type fluorescence probes targeting Aβ species. Experimentally, dicyanomethylene has shown potential for selective binding affinity to Aβ aggregates, along with excellent fluorescence enhancement . Cui et al reported different NIRF probes containing the dicyanomethylene group for targeting Aβ deposits.…”

“…Recently, Zhang Y. and his group demonstrated the mechanism of dicyanomethylene-based fluorescent probes ( Probe 20 ) for Aβ fibril from a theoretical perspective with a combined molecular docking, molecular mechanics, and quantum mechanics approach, along with the quantum chemical method. The report proposed a comprehensive consideration of binding affinity, where the efficiency of the dicyanomethylene-based fluorescent probe for Aβ species could be improved through the combined π-conjugate extension and adjusting the ability of electron donating/accepting groups of the fluorophore . The NIRF probe was also reported with a selective turn-on fluorescence effect when it bound to the target, which may improve the detection of Aβ species and enable in vivo molecular imaging quantitatively.…”