Recent Advances in Computational Approaches for Designing Potential Anti-Alzheimer’s Agents

Gómez-Ganau, Sergi; Julián-Ortiz, Jesús Vicente de; Gozalbes, Rafael

doi:10.1007/978-1-4939-7404-7_2

Cited by 7 publications

(5 citation statements)

References 112 publications

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“…In the quest for multitarget inhibitors for AD therapy, dual inhibitors of BACE1 and glycogen synthase kinase 3 (GSK‐3β) also represent an interesting route. A focused review devoted to this dual inhibition is provided by Rampa et al while a computational focus on the topic was reviewed by Gómez‐Ganau et al as well as by Kumar and Sharma . Nonetheless, early effort on the discovery of dual inhibitors of BACE1 and GSK‐3β, proposed Triazinones and Curcumins as promising chemotypes …”

Section: Multitarget Approaches Involving Secretasementioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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Section: Multitarget Approaches Involving Secretasementioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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“…The “ in silico ” methodology also aids in lowering expenses and speeding up the whole design procedure. 24 − 26 Inspired by multifunctional design and aware of the importance of computational tools, researchers have been using computers to evaluate the therapeutic potential of new compounds that show promise as multitarget AD treatment candidates. 27 − 30 …”

Section: Introductionmentioning

confidence: 99%

“…Using computational tools, we can anticipate a drug’s effectiveness in humans, improve its pharmacokinetic features, identify new targets, and lessen its adverse effects. The “ in silico ” methodology also aids in lowering expenses and speeding up the whole design procedure. − Inspired by multifunctional design and aware of the importance of computational tools, researchers have been using computers to evaluate the therapeutic potential of new compounds that show promise as multitarget AD treatment candidates. − …”

Section: Introductionmentioning

confidence: 99%

Exploring the Multitarget Activity of Wedelolactone against Alzheimer’s Disease: Insights from In Silico Study

et al. 2023

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In this study, Wedelolactone's multitarget activity against Alzheimer's disease was examined using density functional theory and molecular docking techniques. At physiological pH, the pK a and molar fractions have been estimated. The most likely relative rate constants of two radical scavenger mechanisms are formal hydrogen transfer in a lipid environment and single-electron transfer in a water solvent. Compared to Trolox (k overall = 8.96 × 10 4 M −1 s −1 ), Wedelolactone (k overall = 4.26 × 10 9 M −1 s −1 ) is more efficient in scavenging the HOO • radical in an aqueous environment. The chelation capacity of metals was investigated by examining the complexation of the Cu(II) ion at various coordination positions and calculating the complexation kinetic constants. Furthermore, molecular docking simulations showed that the known forms of Wedelolactone at physiological pH effectively inhibited the AChE and BChE enzymes by comparing their activity to that of tacrine (control). Wedelolactone is a promising drug candidate for Alzheimer's disease therapy in light of these findings.

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“…Computerbased methods allow the prediction of therapeutic efficacy in humans, as well as the optimization of pharmacokinetic properties, the discovery of new targets, and the reduction of side effects of the drugs. 29 Moreover, the "in silico" approach helps to reduce costs and to accelerate the overall design process. 17 Attracted by the multifunctional design strategy 17,21,23 and considering the important contribution of computational approaches, the pharmaceutical power of new boron-containing compounds, as good MTD candidates for the treatment of Alzheimer's disease, was computationally explored.…”

Section: Introductionmentioning

confidence: 99%

“…The experimental research, aimed at designing MTDs, is very often complemented with computational analyses, which supply very helpful information in drug discovery. Computer-based methods allow the prediction of therapeutic efficacy in humans, as well as the optimization of pharmacokinetic properties, the discovery of new targets, and the reduction of side effects of the drugs . Moreover, the “in silico” approach helps to reduce costs and to accelerate the overall design process .…”

Section: Introductionmentioning

confidence: 99%

A Boron-Containing Compound Acting on Multiple Targets Against Alzheimer’s Disease. Insights from Ab Initio and Molecular Dynamics Simulations

Ritacca

Ritacco

Dabbish

et al. 2021

J. Chem. Inf. Model.

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Given the multifactorial nature and pathogenesis of Alzheimer's disease, therapeutic strategies are addressed to combine the benefits of every single-target drug into a sole molecule. Quantum mechanics and molecular dynamics (MD) methods were employed here to investigate the multitarget action of a boron-containing compound against Alzheimer's disease. The antioxidant activity as a radical scavenger and metal chelator was explored by means of density functional theory. The most plausible radical scavenger mechanisms, which are hydrogen transfer, radical adduct formation, and single-electron transfer in aqueous and lipid environments, were fully examined. Metal chelation ability was investigated by considering the complexation of Cu(II) ion, one of the metals that in excess can even catalyze the β-amyloid (Aβ) aggregation. The most probable complexes in the physiological environment were identified by considering both the stabilization energy and the shift of the λ max induced by the complexation. The excellent capability to counteract Aβ aggregation was explored by performing MD simulations on protein−ligand adducts, and the activity was compared with that of curcumin, chosen as a reference.

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Recent Advances in Computational Approaches for Designing Potential Anti-Alzheimer’s Agents

Cited by 7 publications

References 112 publications

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Exploring the Multitarget Activity of Wedelolactone against Alzheimer’s Disease: Insights from In Silico Study

A Boron-Containing Compound Acting on Multiple Targets Against Alzheimer’s Disease. Insights from Ab Initio and Molecular Dynamics Simulations

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