Computational modeling and biomarker studies of pharmacological treatment of Alzheimer's disease (Review)

Hassan, Mubashir; Abbas, Qamar; Shahzadi, Saba; Ashwal, Hany Al; Zaki, Nazar; Iqbal, Zeeshan; Moustafa, Ahmed A.

doi:10.3892/mmr.2018.9044

Cited by 17 publications

(18 citation statements)

References 233 publications

(250 reference statements)

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“…Molecular docking experiment is best approach to study the binding conformation of ligands within the active region of target proteins . To predict the best‐fitted conformational position, the synthesized compounds, 8a–k , were docked against alkaline phosphatase.…”

Section: Resultsmentioning

confidence: 99%

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi

Nazir

Ur-Rehman

et al. 2019

Archiv der Pharmazie

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Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide (3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k) with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.

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Section: Resultsmentioning

confidence: 99%

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi

Nazir

Ur-Rehman

et al. 2019

Archiv der Pharmazie

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“…Several computational models of AD pathologies, symptoms and treatments have been proposed, and these are covered in recent comprehensive reviews (see e.g. Cutsuridis and Moustafa, 2017a , 2017b ; Hassan et al, 2018 , and references therein). Several earlier modelling papers in systems and theoretical biology were emphasised more towards understanding the dynamics of Aβ accumulation and its interactions with other proteins ( Hassan et al (2018) ).…”

Section: Towards Multiscale Computational Modelling Of Serotonergic Smentioning

confidence: 99%

“… Cutsuridis and Moustafa, 2017a , 2017b ; Hassan et al, 2018 , and references therein). Several earlier modelling papers in systems and theoretical biology were emphasised more towards understanding the dynamics of Aβ accumulation and its interactions with other proteins ( Hassan et al (2018) ). Later modelling work encompassed the mapping of much larger number of biochemical interactions and other more data-driven, using either logic-based (Maude Petri net) models ( Anastasio, 2011 ).…”

Section: Towards Multiscale Computational Modelling Of Serotonergic Smentioning

confidence: 99%

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

et al. 2020

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Alzheimer's disease (AD) is an age-specific neurodegenerative disease that compromises cognitive functioning and impacts the quality of life of an individual. Pathologically, AD is characterised by abnormal accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein. Despite research advances over the last few decades, there is currently still no cure for AD. Although, medications are available to control some behavioural symptoms and slow the disease's progression, most prescribed medications are based on cholinesterase inhibitors. Over the last decade, there has been increased attention towards novel drugs, targeting alternative neurotransmitter pathways, particularly those targeting serotonergic (5-HT) system. In this review, we focused on 5-HT receptor (5-HTR) mediated signalling and drugs that target these receptors. These pathways regulate key proteins and kinases such as GSK-3 that are associated with abnormal levels of Aβ and tau in AD. We then review computational studies related to 5-HT signalling pathways with the potential for providing deeper understanding of AD pathologies. In particular, we suggest that multiscale and multilevel modelling approaches could potentially provide new insights into AD mechanisms, and towards discovering novel 5-HTR based therapeutic targets.

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“…Molecular docking experiments are the best approach to study the binding conformation of ligands within the active region of target proteins. [31][32][33][34] To predict the best-fitted conformational position of synthesized compounds 5a-o, they were docked against AChE, BChE, jack bean urease and α-glucosidase. The generated docked complexes were examined based on the glide docking energy values (kcal* mol -1 ) and the bonding interaction (hydrogen/hydrophobic) pattern.…”

Section: Docking Energy and Binding Interaction Patternmentioning

confidence: 99%

Structure-activity relationship and in silico study of unique bi-heterocycles: 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole-2-thiol derivatives

Abbasi

Rehman

Siddiqui

et al. 2019

JSCS

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This paper presents the synthesis of some unique bi-heterocyclic hybrid molecules with a thiazole and an oxadiazole ring. The synthesis was initiated by the conversion of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (1) to the corresponding 2-(2-amino-1,3-thiazol-4-yl)acetohydrazide (2) by the reaction with hydrazine hydrate in methanol. The treatment of the acid hydrazide, 2, with carbon disulfide gave the bi-heterocyclic nucleophile, 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole-2-thiol (3). Finally, the target compounds, 5a-o, were synthesized by stirring the nucleophile 3 with different electrophiles, 4a-o, in DMF using LiH as a base and an activator. The structures of the newly synthesized molecules were confirmed through spectroscopic techniques, such as IR, EI-MS, 1 H-NMR and 13 C-NMR. The structure-activity relationship of all these bi-heterocycles was established by evaluating them against four enzymes, namely, acetylcholinesterase, butyrylcholinesterase, urease and α-glucosidase, followed by their in silico study. Moreover, their cytotoxicity was also profiled by killing data of brine shrimps at various concentrations.

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Computational modeling and biomarker studies of pharmacological treatment of Alzheimer's disease (Review)

Cited by 17 publications

References 233 publications

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

Structure-activity relationship and in silico study of unique bi-heterocycles: 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole-2-thiol derivatives

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