Abstract:Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine.Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electr… Show more
“…The higher affinity exhibited by CO compared to CH and SA can be due to the faster association phase. Our data are in agreement with a previous study [ 80 ] that showed the ability of berberine-like inhibitors of Aβ 1-42 to interact with the polypeptide at low micromolar K D values [ 80 ]. Fig.…”
Section: Resultssupporting
confidence: 93%
“…4 ) suggested the formation of complexes, in a concentration-dependent manner. Freshly dissolved Aβ 1-42, after HFIP treatment, was covalently immobilized on Sensor chip [ 80 ]. Kinetic parameters, reported in Table 1 , allowed the estimation of thermodynamic dissociation constant values that appear in the low, for CO, high, for SA, and very high, for CH, micromolar range.…”
Herein we present a comparative study of the effects of isoquinoline alkaloids belonging to benzo [
c
]phenanthridine and berberine families on β-amyloid aggregation. Results obtained using a Thioflavine T (ThT) fluorescence assay and circular dichroism (CD) spectroscopy suggested that the benzo [
c
]phenanthridine nucleus, present in both sanguinarine and chelerythrine molecules, was directly involved in an inhibitory effect of Aβ
1–42
aggregation. Conversely, coralyne, that contains the isomeric berberine nucleus, significantly increased propensity for Aβ
1–42
to aggregate. Surface Plasmon Resonance (SPR) experiments provided quantitative estimation of these interactions: coralyne bound to Aβ
1–42
with an affinity (K
D
= 11.6 μM) higher than benzo [
c
]phenanthridines. Molecular docking studies confirmed that all three compounds are able to recognize Aβ
1–42
in different aggregation forms suggesting their effective capacity to modulate self-recognition mechanism. Molecular dynamics simulations indicated that coralyne increased the β-content of Aβ
1–42
, in early stages of aggregation, consistently with fluorescence-based promotion of self-recognition mechanism by this alkaloid. At the same time, sanguinarine seemed to determine an increase of helical conformation corroborating its ability to delay aggregation as experimentally proved
in vitro
. Investigated compounds demonstrated to interfere with aggregation of Aβ
1–42
applying as starting leads in neurodegenerative diseases.
“…The higher affinity exhibited by CO compared to CH and SA can be due to the faster association phase. Our data are in agreement with a previous study [ 80 ] that showed the ability of berberine-like inhibitors of Aβ 1-42 to interact with the polypeptide at low micromolar K D values [ 80 ]. Fig.…”
Section: Resultssupporting
confidence: 93%
“…4 ) suggested the formation of complexes, in a concentration-dependent manner. Freshly dissolved Aβ 1-42, after HFIP treatment, was covalently immobilized on Sensor chip [ 80 ]. Kinetic parameters, reported in Table 1 , allowed the estimation of thermodynamic dissociation constant values that appear in the low, for CO, high, for SA, and very high, for CH, micromolar range.…”
Herein we present a comparative study of the effects of isoquinoline alkaloids belonging to benzo [
c
]phenanthridine and berberine families on β-amyloid aggregation. Results obtained using a Thioflavine T (ThT) fluorescence assay and circular dichroism (CD) spectroscopy suggested that the benzo [
c
]phenanthridine nucleus, present in both sanguinarine and chelerythrine molecules, was directly involved in an inhibitory effect of Aβ
1–42
aggregation. Conversely, coralyne, that contains the isomeric berberine nucleus, significantly increased propensity for Aβ
1–42
to aggregate. Surface Plasmon Resonance (SPR) experiments provided quantitative estimation of these interactions: coralyne bound to Aβ
1–42
with an affinity (K
D
= 11.6 μM) higher than benzo [
c
]phenanthridines. Molecular docking studies confirmed that all three compounds are able to recognize Aβ
1–42
in different aggregation forms suggesting their effective capacity to modulate self-recognition mechanism. Molecular dynamics simulations indicated that coralyne increased the β-content of Aβ
1–42
, in early stages of aggregation, consistently with fluorescence-based promotion of self-recognition mechanism by this alkaloid. At the same time, sanguinarine seemed to determine an increase of helical conformation corroborating its ability to delay aggregation as experimentally proved
in vitro
. Investigated compounds demonstrated to interfere with aggregation of Aβ
1–42
applying as starting leads in neurodegenerative diseases.
“…Among the numerous classes of compounds, mostly related to traditional DNA binders, that have been successfully developed as G4-DNA ligands [17], the natural product berberine (1a) has attracted special attention. Berberine (1a) is an isoquinoline alkaloid with an exceptionally wide range of biological activities [23,24]. It has been shown that berberine (1a) and its derivatives act, for example, as anti-inflammatory [25], antibacterial [26,27], and anticancer reagents [28,29].…”
A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K
b values of 10–11 (2:1) and 5–6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand–G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.
“…However, the BACE1 inhibitory activity of berberine (11) was found to be less (IC 50 value > 100 µM) [67]. In another study, through surface plasmon resonance (SPR) binding analysis and docking studies, the direct binding of berberine and BACE-1 was illustrated [68]. Reports of berberine acting on the BACE1 expression levels are also available, hence, further studies are required for the identification of the potential mechanism of action of the compound [69].…”
Section: Alkaloids Showing Inhibition Of Beta-site Amyloid Precursor mentioning
Alzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.
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