A molecular approach in drug development for Alzheimer’s disease

Agatonović-Kuštrin, Snežana; Kettle, Christine; Morton, David W.

doi:10.1016/j.biopha.2018.06.147

Cited by 184 publications

(127 citation statements)

References 170 publications

Supporting

Mentioning

122

Contrasting

Unclassified

Order By: Relevance

“…The effect of drugs as well as biochemical processes in organism quite often is different from the expected and depends on patient's condition, presence of accompanying diseases, or type of pathology, and the receptor systems of target cells forced to change adjusting to a new state . Therefore, a complex study should include an expected pathological condition models (stress, morbid state, or model of complicated pathology).…”

Section: Discussionmentioning

confidence: 99%

An integrated approach to study the molecular aspects of regulatory peptides biological mechanism

V’yunova

Andreeva

Шевченко

et al. 2019

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

An integrated methodological approach to study the molecular aspects of short regulatory neuropeptides biological mechanism is proposed. The complex research is based on radioligand-receptor method of analysis and covers such points of peptides molecular activity as: specific binding of peptides to brain cells plasmatic membranes, formation of tissue specific synacton, influence of peptides (as allosteric modulators) on functionality of different neuroreceptors as well as delayed in time effects of peptides on receptor-binding activity of well-known neuroreceptor systems. Radiolabeled ligands in such complex study are the one of the best and precision instruments to uncover the molecular mechanism of multiple and multitarget biological effects of regulatory peptides. In this issue we used heptapeptide Semax as a model regulatory peptide, [ 3 H]Ach and [ 3 H]GABA as an effector molecules, and the rat model of stress-induced memory and behavior impairment as a morbid state. We showed the ability of Semax to modulate in a dose-dependent manner [ 3 H] Ach and [ 3 H]GABA specific binding to some of its corresponding receptors as well as to affect the number of [ 3 H]GABA specific binding places on rat neurons plasmatic membranes after complex stress exposure.

show abstract

Section: Discussionmentioning

confidence: 99%

An integrated approach to study the molecular aspects of regulatory peptides biological mechanism

V’yunova

Andreeva

Шевченко

et al. 2019

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

show abstract

“…Enhanced sampling MD and conformational analysis optimized for disordered targets, coupled with computational docking and machine learning were employed to successfully identify novel chemically diverse Tau ligands including an inhibitor that delays the in vitro aggregation reaction without affecting the amount of aggregate formed at the steady state [166]. Other CADD studies for the development of anti-Tau inhibitors are summarized in previously published review articles [167,168].…”

Section: Cadd For the Development Of Anti-tau Inhibitorsmentioning

confidence: 99%

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Mouchlis

Melagraki

Zacharia

et al. 2020

IJMS

View full text Add to dashboard Cite

Aging-associated neurodegenerative diseases, which are characterized by progressive neuronal death and synapses loss in human brain, are rapidly growing affecting millions of people globally. Alzheimer’s is the most common neurodegenerative disease and it can be caused by genetic and environmental risk factors. This review describes the amyloid-β and Tau hypotheses leading to amyloid plaques and neurofibrillary tangles, respectively which are the predominant pathways for the development of anti-Alzheimer’s small molecule inhibitors. The function and structure of the druggable targets of these two pathways including β-secretase, γ-secretase, and Tau are discussed in this review article. Computer-Aided Drug Design including computational structure-based design and ligand-based design have been employed successfully to develop inhibitors for biomolecular targets involved in Alzheimer’s. The application of computational molecular modeling for the discovery of small molecule inhibitors and modulators for β-secretase and γ-secretase is summarized. Examples of computational approaches employed for the development of anti-amyloid aggregation and anti-Tau phosphorylation, proteolysis and aggregation inhibitors are also reported.

show abstract

“…Previous work has revealed that the albumin‐derived peptide KLPGF can inhibit the activity of AChE effectively with an inhibition value of 61.23 ± 4.73% at a concentration of 50 μg L −1 . Currently, the multi‐target directed ligand (MTDL) strategy for AD has attracted more attention …”

Section: Introductionmentioning

confidence: 99%

“…17 Currently, the multi-target directed ligand (MTDL) strategy for AD has attracted more attention. 18,19 According to the reports mentioned above, the main purpose of this study is to find novel AD-inhibitory dipeptides and tripeptides from ovalbumin using in silico virtual screening technology and molecular docking. Furthermore, the CDOCKER program in Discovery Studio 2017 is used to analyze the interaction mechanism of peptides with targets (i.e., AChE, BChE, and BACE1).…”

Section: Introductionmentioning

confidence: 99%

Identification of ovalbumin‐derived peptides as multi‐target inhibitors of AChE, BChE, and BACE1

Dong

et al. 2020

J Sci Food Agric

View full text Add to dashboard Cite

BACKGROUND Alzheimer's disease (AD) is a kind of progressive neurodegenerative disease that affects the elderly. There is no ideal treatment for AD. Thus, the purpose of this study is to identify anti‐AD peptides from ovalbumin. RESULTS The potential tripeptides IEK, LYR, and CIK were selected for molecular docking. The ‘‐CDOCKER_Energy’ values of the best docking positions of the tripeptide IEK, LYR, and CIK interacting with acetylcholinesterase (AChE) were 93.8119, 86.9556 and 73.6370 kcal mol−1, respectively. The ‘‐CDOCKER_Energy’ values for interaction with butyrylcholinesterase (BChE) were 96.6386, 80.8392, and 87.4341 kcal mol−1, respectively. Most importantly, the ‘‐CDOCKER_Energy’ values for interaction with β‐site amyloid precursor protein cleavage enzyme1 (BACE1) were 85.5903, 71.3342, and 68.4290 kcal mol−1, respectively. Overall, in vitro assay results demonstrated that the peptide CIK exhibited impressive inhibitory activities against AChE, BChE, and BACE1, with half maximal inhibitory concentration (IC50) values of 6.76, 7.72, and 34.48 μmol L−1, respectively. In particular, CIK can be joined with some peripheral anion sites (PAS) and catalytic sites on AChE, BChE, and BACE1. CONCLUSION Tripeptide CIK can effectively inhibit the activities of AChE, BChE, and BACE1. Tripeptide CIK therefore has the potential to treat AD effectively. © 2020 Society of Chemical Industry

show abstract

A molecular approach in drug development for Alzheimer’s disease

Cited by 184 publications

References 170 publications

An integrated approach to study the molecular aspects of regulatory peptides biological mechanism

An integrated approach to study the molecular aspects of regulatory peptides biological mechanism

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Identification of ovalbumin‐derived peptides as multi‐target inhibitors of AChE, BChE, and BACE1

Contact Info

Product

Resources

About