Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with <i>β</i>‐Amyloid Aggregation

Brogi, Simone; Butini, Stefania; Maramai, Samuele; Colombo, Raffaella; Verga, Laura; Lanni, Cristina; Lorenzi, Ersilia De; Lamponi, Stefania; Andreassi, Marco; Bartolini, Manuela; Andrisano, Vincenza; Novellino, Ettore; Campiani, Giuseppe; Brindisi, Margherita; Gemma, Sandra

doi:10.1111/cns.12290

Cited by 53 publications

(42 citation statements)

References 41 publications

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“…The dysregulation of the biosynthesis of acetylcholine neurotransmitter has been found in AD (Brogi et al 2014;Rosini et al 2014). Anti-acetylcholinesterases, which inhibit the action of the acetylcholinesterase enzyme that breaks down acetylcholine and increase the level, duration, and action of acetylcholine, have been suggested to improve learning and memory.…”

Section: Inhibitors and Modulators Of Neurotransmittersmentioning

confidence: 99%

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Thapa

2015

Advances in Experimental Medicine and Biology

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Flavonoids are naturally occurring phytochemicals found in a variety of fruits and vegetables and offer color, flavor, aroma, nutritional and health benefits. Flavonoids have been found to play a neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) peptide into oligomers and fibrils, which are linked to the pathogenesis of Alzheimer's disease. The neuroprotective efficacy of flavonoids has been found to strongly depend on their structure and functional groups. Flavonoids may exist in monomeric, as well as di-, tri-, tetra- or polymeric form through C-C or C-O-C linkages. It has been shown that flavonoids containing two or more units, e.g., biflavonoids, exert greater biological activity than their respective monoflavonoids. For instance, biflavonoids have the ability to distinctly alter Aβ aggregation and more effectively reduce the toxicity of Aβ oligomers compared to the monoflavonoid moieties. Although the molecular mechanisms remain to be elucidated, flavonoids have been shown to alter the Aβ aggregation pathway to yield non-toxic, unstructured Aβ aggregates, as well as directly exerting a neuroprotective effect to cells. In this chapter, we review biflavonoid-mediated Aβ aggregation and toxicity, and highlight the beneficial roles biflavonoids can potentially play in the prevention and treatment of Alzheimer's disease.

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Section: Inhibitors and Modulators Of Neurotransmittersmentioning

confidence: 99%

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Thapa

2015

Advances in Experimental Medicine and Biology

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“…It is reported in the literature that the rearrangement of β‐strands lead to destabilization of Aβ 42 protofibril structure . As depicted in Figure a, the distance between A21 (chain A) and V36 (chain B) was significantly increased to ∼1.75 nm in Aβ 42 protofibril‐ C1 complex as compared to ∼1.20 nm in Aβ 42 protofibril.…”

Section: Resultsmentioning

confidence: 76%

“…For Aβ 42 protofibril, D23‐K28 interchain salt bridge distance remain close to ∼0.30 nm throughout simulation while the distance approaches ∼0.60 nm for Aβ 42 protofibril‐ C1 complex (Figure a‐b). Thus, C1 disrupt salt bridge interaction between chains A−B and hence cause destabilization of Aβ 42 protofibril structure, which is consistent with the reported studies …”

Section: Resultsmentioning

confidence: 99%

Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ₄₂ Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

2017

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The self‐assembly of amyloid β‐peptide (Aβ) into β‐sheet enriched fibrillar aggregates is associated with Alzheimer's disease (AD). A disease modifying therapy for AD involves a search for inhibitors that can inhibit Aβ aggregation. Previous studies reported that compound C1 (J147 derivative) strongly inhibit Aβ aggregation and disassemble preformed fibrils, however, the underlying inhibitory mechanism remains elusive. In this regard, the molecular mechanism behind the anti‐aggregation activity of C1 has been investigated using molecular docking and molecular dynamics (MD) simulations. C1 effectively binds to central hydrophobic core (CHC) region i. e. KLVFF (16‐20) of Aβ42 monomer and inhibit its conformational transition into aggregation prone β‐conformation. C1 destabilize Aβ42 protofibril structure by increasing the interchain distance between chains A−B, disrupting the salt‐bridge interaction between D23‐K28 and decreasing the number of backbone hydrogen bonds between chains A−B of Aβ42 protofibril. The present study provides a complete picture of the inhibitory mechanism of C1 against Aβ42 oligomer formation and fibril disassembly.

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“…The technique was applied using the docking complexes obtained by means of Glide. The software was used to calculate the free-binding energy (DG bind ) of each ligand, as recently reported by us [32][33][34] .…”

Section: Prime/mm-gbsa Simulationmentioning

confidence: 99%

Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

Brindisi

Brogi

Giovani

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Metallo-b-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to b-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based highthroughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.

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Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β‐Amyloid Aggregation

Abstract: Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

Cited by 53 publications

References 41 publications

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ₄₂ Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

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Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β‐Amyloid Aggregation

Abstract: Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

Cited by 53 publications

References 41 publications

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ42 Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

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About

Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ₄₂ Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study