313 results on '"β secretase"'
Search Results
2. Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction.
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Pandey, Anjali, Bani, Sarang, Dutt, Prabhu, Kumar Satti, Naresh, Avtar Suri, Krishan, and Nabi Qazi, Ghulam
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ALZHEIMER'S disease , *NEUROPROTECTIVE agents , *PHARMACODYNAMICS , *COGNITION disorders , *WITHANIA somnifera - Abstract
Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of β amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid β-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both β- and γ- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Aβ processing, protection against oxidative stress and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]
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- 2018
- Full Text
- View/download PDF
3. Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360
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Jean-Michel Rondeau, Heinrich Rueeger, Rainer Martin Lueoend, Laura H. Jacobson, Markus Voegtle, Rainer Machauer, Grit Laue, Philipp Holzer, Konstanze Hurth, Siem Jacob Veenstra, Matthias Staufenbiel, Marina Tintelnot-Blomley, Ulf Neumann, and Mathias Frederiksen
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Central nervous system ,Thiazines ,Molecular Dynamics Simulation ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,Alzheimer Disease ,Oxazines ,Drug Discovery ,medicine ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Potency ,Enzyme Inhibitors ,Picolinic Acids ,030304 developmental biology ,0303 health sciences ,Amyloid beta-Peptides ,Binding Sites ,Trifluoromethyl ,Treatment regimen ,Brain ,Penetration (firestop) ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,chemistry ,β secretase ,Molecular Medicine ,Efflux ,Amyloid Precursor Protein Secretases ,Lead compound ,Half-Life - Abstract
Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens.
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- 2021
4. Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020)
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Frederik J. R. Rombouts, Harrie J.M. Gijsen, Chien-Chi Hsiao, and Ken-Ichi Kusakabe
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Amyloid ,Patent literature ,01 natural sciences ,Patents as Topic ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,Alzheimer Disease ,mental disorders ,Drug Discovery ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Pharmacology ,chemistry.chemical_classification ,biology ,Chemistry ,General Medicine ,Small molecule ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,Biochemistry ,030220 oncology & carcinogenesis ,β secretase ,biology.protein ,Amyloid Precursor Protein Secretases - Abstract
Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been extensively pursued as potential disease-modifying treatment for Alzheimer's disease (AD). Clinical failures with BACE inhibitors have progressively raised the bar forever cleaner candidates with reduced cardiovascular liability, toxicity risk, and increased selectivity over cathepsin D (CatD) and BACE2.This review provides an overview of patented BACE1 inhibitors between 2011 and 2020 per pharmaceutical company or research group and highlights the progress that was made in dialing out toxicity liabilities.Despite an increasingly crowded IP situation, significant progress was made using highly complex chemistry in avoiding toxicity liabilities, with BACE1/BACE2 selectivity being the most remarkable achievement. However, clinical trial data suggest on-target toxicity is likely a contributing factor, which implies the only potential future of BACE1 inhibitors lies in careful titration of highly selective compounds in early populations where the amyloid burden is still minimal as prophylactic therapy, or as an affordable oral maintenance therapy following amyloid-clearing therapies.
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- 2020
5. Unique, yet Typical Oxyanion Holes in Aspartic Proteases
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Mark Aldren M. Feliciano and Brian Gold
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Protease ,biology ,010405 organic chemistry ,Chemistry ,medicine.medical_treatment ,Human immunodeficiency virus (HIV) ,Oxyanion ,General Chemistry ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Pepsin ,HIV-1 protease ,Biochemistry ,Aspartate protease ,medicine ,biology.protein ,β secretase ,Oxyanion hole - Abstract
From studies on pepsin nearly 200 years ago to the modern pursuit of drugs targeting renin, HIV protease, and β-secretases, aspartic proteases continue to shape the understanding of proteins. Thoug...
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- 2020
6. Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors
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Darren L. Riley, Andre Stander, CJ Van der Westhuizen, Steenkamp, DG Van Greunen, Jenny-Lee Panayides, Margo Nell, and Werner Cordier
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Indole test ,Chemistry ,Stereochemistry ,Organic Chemistry ,Industrial research ,β secretase - Abstract
This work was supported by the National Research Foundation (NRF) of South Africa (Thuthuka grant number 106959), the University of Pretoria (Research and Development Program) and the Council for Scientific and Industrial Research (CSIR), South Africa.
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- 2020
7. Synthesis of piperidine-4-one Derivative Containing Dipeptide: An Acetyl cholinesterase and β-secretase Inhibitor
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Vasudevan Mani, Veerachamy Alagarsamy, Damodar Nayak Ammunje, Jithendra Chimakurthy, Theivendren Panneerselvam, Selvaraj Kunjiappan, Govindaraj Saravanan, Parasuraman Pavadai, Suresh Ramalingam, and Pandurangan Perumal
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Pharmacology ,030506 rehabilitation ,Dipeptide ,Stereochemistry ,05 social sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,β secretase ,0501 psychology and cognitive sciences ,Acetyl cholinesterase ,Piperidine ,0305 other medical science ,Derivative (chemistry) ,050104 developmental & child psychology - Abstract
Background: With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized novel piperidone fused dipeptide (DPPS) derivatives possessing dual action such as acetylcholinesterase (AChE) and beta-amyloid peptide (Aβ) aggregation inhibition. Designed peptide was synthesized by solid phase peptide synthesis using FMOC chemistry protocol and characterized by mass spectroscopy. Methods: The amino acid sequence in peptide was analyzed by LC-MS-MS. In silico docking analysis was carried out using GLIDE software. The docking score using GLIDE was found to be -7.88 against AChE and -9.74 against BACE1 enzyme. In vitro enzyme inhibition assay was carried out for AChE enzyme and BACE1 enzyme. Results: The IC50 values of AChE inhibition and BACE1 of DPPS were found to be 0.4796 μM/ml and 0.0154 μM/ml, respectively. The correlation of in silico and in vitro results showed that DPPS possessed a greater ability to inhibit BACE1 enzyme.
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- 2020
8. Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease
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Anja Pišlar, Anna Więckowska, Barbara Malawska, Paula Zaręba, Raimon Sabaté, Dawid Panek, Jakub Jończyk, Tomasz Wichur, Natalia Szałaj, Anna Pasieka, Krzysztof Więckowski, Justyna Godyń, and Marek Bajda
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Pharmacology ,cholinesterase inhibitors ,010405 organic chemistry ,business.industry ,Multifunctional ligands ,RM1-950 ,General Medicine ,Disease ,Computational biology ,multifunctional ligands ,01 natural sciences ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Multi target ,Drug Discovery ,β secretase ,β-secretase ,Medicine ,Identification (biology) ,5-ht6 receptor antagonists ,Therapeutics. Pharmacology ,business - Abstract
Effective therapy of Alzheimer’s disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands – 5-HT6 receptor antagonists and cholinesterase inhibitors – with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their β-secretase, tau, and amyloid β aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid β aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 Ki=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.
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- 2020
9. Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease
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Ulf Neumann, Rainer Machauer, Markus Voegtle, Marina Tintelnot-Blomley, Konstanze Hurth, Grit Laue, Siem Jacob Veenstra, Rainer Martin Lueoend, Karen Beltz, Jean-Michel Rondeau, Laura H. Jacobson, and Heinrich Rueeger
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Male ,Central nervous system ,Disease ,Pharmacology ,Cell Line ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Dogs ,Pharmacokinetics ,Alzheimer Disease ,Drug Discovery ,Oxazines ,medicine ,Potency ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Enzyme Inhibitors ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,Rats ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,β secretase ,Molecular Medicine ,Efflux ,Amyloid Precursor Protein Secretases ,Lead compound - Abstract
After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.
- Published
- 2021
10. Multiple mechanisms of age-dependent accumulation of amyloid beta protein in rat brain: Prevention by dietary supplementation with N-acetylcysteine, α-lipoic acid and α-tocopherol.
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Sinha, Maitrayee, Bir, Aritri, Banerjee, Anindita, Bhowmick, Pritha, and Chakrabarti, Sasanka
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AMYLOID beta-protein , *DIETARY supplements , *LIPOIC acid , *VITAMIN E content of food , *AGING , *BRAIN , *ALZHEIMER'S disease treatment , *LABORATORY mice - Abstract
The aged brain may be used as a tool to investigate altered metabolism of amyloid beta protein (Aβ42) that may have implications in the pathogenesis of Alzheimer's disease (AD). In the present study, we have observed a striking increase in the amyloid precursor protein (APP) level in the brain cortex of aged rats (22–24 months) along with a mild but statistically significant increase in the level of APP mRNA. Moreover, the activity of β secretase is elevated (nearly 55%) and that of neprilysin diminished (48%) in brain cortex of aged rats compared to that in young rats (4–6 months). All these changes lead to a markedly increased accumulation of Aβ42 in brain cortical tissue of aged rats. Long-term dietary supplementation of rats with a combination of N-acetylcysteine, α-lipoic and α-tocopherol from 18 months onwards daily till the sacrifice of the animals by 22–24 months, attenuates the age-related alterations in amyloid beta metabolism. In separate experiments, a significant impairment of spatial learning and memory has been observed in aged rats, and the phenomenon is remarkably prevented by the dietary supplementation of the aged animals by the same combination of N-acetylcysteine, α-lipoic acid and α-tocopherol. The results call for further explorations of this combination in suitable animal models in ameliorating AD related brain deficits. [ABSTRACT FROM AUTHOR]
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- 2016
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- View/download PDF
11. Overcoming Challenging Substituent Perturbations with Multisite λ-Dynamics: A Case Study Targeting β-Secretase 1
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Jonah Z. Vilseck, Noor Sohail, Ryan L. Hayes, and Charles L. Brooks
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Materials science ,Substituent ,Molecular Dynamics Simulation ,Ligands ,010402 general chemistry ,01 natural sciences ,Article ,Force field (chemistry) ,chemistry.chemical_compound ,0103 physical sciences ,Aspartic Acid Endopeptidases ,Humans ,Degree of precision ,General Materials Science ,Atomic charge ,Physical and Theoretical Chemistry ,Binding Sites ,010304 chemical physics ,Protein Structure, Tertiary ,0104 chemical sciences ,chemistry ,Drug Design ,β secretase ,Thermodynamics ,Amyloid Precursor Protein Secretases ,Biological system - Abstract
Alchemical free energy calculations have made a dramatic impact upon the field of structure-based drug design by allowing functional group modifications to be explored computationally prior to experimental synthesis and assay evaluation, thereby informing and directing synthetic strategies. In furthering the advancement of this area, a series of 21 β-secretase 1 (BACE1) inhibitors developed by Janssen Pharmaceuticals were examined to evaluate the ability to explore large substituent perturbations, some of which contain scaffold modifications, with multisite λ-dynamics (MSλD), an innovative alchemical free energy framework. Our findings indicate that MSλD is able to efficiently explore all structurally diverse ligand end-states simultaneously within a single MD simulation with a high degree of precision and with reduced computational costs compared to the widely used approach TI/MBAR. Furthermore, computational predictions were shown to be accurate to within 0.5-0.8 kcal/mol when CM1A partial atomic charges were combined with CHARMM or OPLS-AA-based force fields, demonstrating that MSλD is force field independent and a viable alternative to FEP or TI approaches for drug design.
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- 2019
12. BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease
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Hany A. Omar, Shifaa M. Abdin, Taleb H. Al-Tel, Hasan Alniss, and Nour M Moussa-Pacha
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Drug ,Amyloid β ,media_common.quotation_subject ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,mental disorders ,Drug Discovery ,Amyloid precursor protein ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Enzyme Inhibitors ,030304 developmental biology ,media_common ,Pharmacology ,Clinical Trials as Topic ,0303 health sciences ,Amyloid beta-Peptides ,biology ,business.industry ,Neurodegeneration ,medicine.disease ,Biochemistry of Alzheimer's disease ,Clinical trial ,030220 oncology & carcinogenesis ,β secretase ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,business ,Neuroscience - Abstract
Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β-site APP cleaving enzyme-1 (BACE1), which is involved in the rate-limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ-secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD-3293, JNJ-54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.
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- 2019
13. Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors
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Satya P. Gupta, Monika Chauhan, Kirtika Madan, Sarvesh Paliwal, Swapnil Sharma, and Richa Arya
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0301 basic medicine ,chemistry.chemical_classification ,Stereochemistry ,Pharmaceutical Science ,Cleavage (embryo) ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Enzyme ,chemistry ,Docking (molecular) ,Drug Discovery ,β secretase ,Molecular Medicine ,Pharmacophore ,030217 neurology & neurosurgery - Abstract
Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.
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- 2019
14. Iron-mediated site-selective oxidative C–H/C–H cross-coupling of aryl radicals with quinones: synthesis of β-secretase-1 inhibitor B and related arylated quinones
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Sakthivel Pandaram, Andivelu Ilangovan, and Adarsh Krishna T P
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Aqueous solution ,010405 organic chemistry ,Aryl ,Radical ,Organic Chemistry ,One-pot synthesis ,Oxidative phosphorylation ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Lipophilicity ,β secretase ,Site selective - Abstract
Phenoxy radicals generated from substituted arenes were converted into para site selective C-aryl radicals and coupled with quinones, using an inexpensive FeCl3–K2S2O8 system, to obtain several arylated quinones, in good to moderate yields, under operationally simple and mild conditions. This method is useful for one pot synthesis of β-secretase-1 (BACE) inhibitor B. The arylated quinones were used as intermediates in the synthesis of phenothiazin-5-ones. Theoretical studies on the pharmacokinetic properties of phenothiazin-5-ones showed high lipophilicity (log p = 3.69), poor water solubility (log s = −6.42), and high gastrointestinal absorption (GI).
- Published
- 2019
15. β-secretase 1 inhibitory activity and AMP-activated protein kinase activation of Callyspongia samarensis extracts
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Allan Patrick G. Macabeo, Mary Jho-Anne T Corpuz, Analin Empaynado Porto, Hsi-Ya Huang, Danica L Resuello, Stephen Lirio, and Oliver B. Villaflores
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biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,AMPK ,Plant Science ,Blood–brain barrier ,Inhibitory postsynaptic potential ,biology.organism_classification ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,AMP-activated protein kinase ,Callyspongia ,medicine ,β secretase ,biology.protein ,IC50 - Abstract
The methanolic extract of Callyspongia samarensis (MCS) significantly inhibited β-secretase 1 (IC50 99.82 µg/mL) in a dose-dependent manner and demonstrated a noncompetitive type of inhibition. Furthermore, it exhibited the highest AMPK activation (EC50 14.47 μg/mL) as compared with the standard, Aspirin (EC50 >100 μg/mL). HPLC/ESI-MS analysis of MCS extract revealed 15 peaks, in which nine peaks demonstrated similar fragmentation pattern with the known compounds in literature and in database library: 5-aminopentanoic acid (1), 4-aminobutanoic acid (3), Luotonin A (4), (E)-3-(1H-imidazol-5-yl) prop-2-enoic acid (8), Galactosphingosine (10), D-sphingosine (11), 5,7,4′-trihydroxy-3′,5′-dimethoxyflavone (12), hydroxydihydrovolide (13), and 3,5-dibromo-4-methoxyphenylpyruvic acid (14); and 6 peaks are not identified (2, 5–7, 9, and 15). Acute oral toxicity test of MCS extract revealed that it is nontoxic, with an LD50 of >2000 mg/kg. Assessment of BBB permeability of MCS extract showed that compound 15 was able to cross the BBB making it a suitable candidate for developing CNS drugs.
- Published
- 2018
16. Application of molecular framework-based data-mining method in the search for beta-secretase 1 inhibitors through drug repurposing
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George Nicolae Daniel Ion, George Mihai Nitulescu, Gina Lupascu, and Dragos Paul Mihai
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0301 basic medicine ,Amyloid ,Computational biology ,01 natural sciences ,03 medical and health sciences ,Structural Biology ,mental disorders ,Data Mining ,Humans ,Protease Inhibitors ,Molecular Biology ,Virtual screening ,biology ,010405 organic chemistry ,Chemistry ,Drug Repositioning ,General Medicine ,0104 chemical sciences ,Molecular Docking Simulation ,Drug repositioning ,HEK293 Cells ,030104 developmental biology ,Beta-secretase 1 ,ROC Curve ,biology.protein ,β secretase ,Amyloid Precursor Protein Secretases - Abstract
Targeting beta-secretase 1, also known as beta-amyloid precursor protein-cleaving enzyme (BACE-1) for the inhibition of amyloid production, has been intensely studied in the last decades in the search for stopping Alzheimer's disease (AD) progression. The chances of finding a druggable BACE-1 inhibitor may be increased by drug repurposing, as this kind of molecules already fulfil certain requirements needed for further advancement. The study describes the development and application of a data-mining method based on molecular frameworks and descriptor values of tested BACE-1 inhibitors, suitable for filtering large compound databases, in order to find molecules with high potency against this protease. A total of 465 compounds extracted from the literature, tested against BACE-1, were analysed for finding molecular descriptor values and frameworks that ensure a high probability of strong inhibition. Resulting conclusions were used for filtering DrugBank database, containing ∼8700 approved and experimental drugs, obtaining 26 structures characterized by four major Bemis-Murcko frameworks: 2-[3-(2-cyclohexylethyl)cyclohexyl]-decahydronaphthalene, 3-(2-cyclohexylethyl)-1,1'-bi(cyclohexane), [5-(cyclohexylmethyl)-8-cyclopentyloctyl]cyclohexane and (3-cyclohexylcyclopentyl)cyclohexane. The compounds were further studied by molecular docking using the structure of the closed form of the enzyme, which revealed seven compounds already involved in trials targeting BACE-1 inhibition, confirming the method's specificity. The compounds that afforded the best binding energies were DB06925 (tyrosine-protein kinase inhibitor), DB12285 (Verubecestat) and DB08899 (Enzalutamide). Moreover, docking results indicated several other molecules with high
- Published
- 2018
17. Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective β-Secretase (BACE1) Inhibitors over BACE2
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Kazuki Fujimoto, Shigeru Ando, Yutaka Tonomura, Shuhei Yoshida, Harrie J.M. Gijsen, Shiho Yamamoto, Diederik Moechars, Naoki Kanegawa, Frederik J. R. Rombouts, Hisanori Ito, Kouki Fuchino, Shinji Suzuki, Takahiko Yamamoto, Eriko Matsuoka, Genta Tadano, Naoya Asada, and Ken-ichi Kusakabe
- Subjects
Propynyl ,01 natural sciences ,Cocrystal ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,Oxazines ,Molecule ,Aspartic Acid Endopeptidases ,Humans ,Enzyme Inhibitors ,030304 developmental biology ,0303 health sciences ,Chemistry ,Water ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Design ,β secretase ,Molecular Medicine ,Verubecestat ,Structure based ,Amyloid Precursor Protein Secretases ,Selectivity ,High homology - Abstract
BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine 3 with improved selectivity. Further optimization efforts led to the discovery of compound 6 with high selectivity. The cocrystal structures of 7, a close analogue of 6, bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity.
- Published
- 2021
18. Plant-Based β-Secretase (BACE-1) Inhibitors: A Mechanistic Approach to Encounter Alzheimer’s Disorder
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Raja Chakraborty, Saikat Sen, and Atanu Bhattacharjee
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chemistry.chemical_classification ,Drug ,Natural product ,biology ,Drug discovery ,media_common.quotation_subject ,Peptide ,Pharmacology ,In vitro ,chemistry.chemical_compound ,chemistry ,In vivo ,Amyloid precursor protein ,biology.protein ,β secretase ,media_common - Abstract
BACE-1 (β-secretase) has emerged as a promising drug to treat Alzheimer’s disease (AD). BACE-1, an aspartic protease, acts on amyloid precursor protein (APP) prompting the formation and deposition of amyloid-β peptide (Aβ). BACE-1 hindrance has direct ramifications in AD pathology without generally influencing viability. However, inhibition of BACE-1 specifically through in vivo models has introduced numerous issues to the researchers. Since its identification in 2000, inhibitors covering a wide range of auxiliary classes have been structured and created. Advancement in these fields brought about targeted drug therapy that may reduce deposition of Aβ plaque in the brain. Natural product derivatives have always been a potential source of drug discovery process, and they are considered to be safe and economical. Flavonoids are an abundance of naturally delivered BACE-1 inhibitors. Citrus bioflavonoids are distinguished as potential noncompetitive BACE-1 inhibitors. Further, xanthones displayed the hindrance of Aβ conglomeration and BACE-1 activity in vitro and in cells, notwithstanding their radical scavenging and metal chelation capacity. The manuscript has been focused to deliver a refreshed learning with array of phytoextracts and lead molecules with BACE-1 inhibitory potential.
- Published
- 2021
19. Biginelli Reaction and β‐Secretase Inhibition: A Multicomponent Reaction as a Friendly Educational Approach to Bioactive Compounds
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Federico Berti, Iole Cerminara, Fulvia Felluga, Paolo Lupattelli, Lucia Chiummiento, Maria Funicello, Funicello, Maria, Cerminara, Iole, Chiummiento, Lucia, Lupattelli, Paolo, Felluga, Fulvia, and Berti, Federico
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Hands-On Learning/Manipulative ,Computer science ,first-year undergraduate/general ,education ,Biginelli reaction ,enzymes ,Graduate Education/Research ,combinatorial chemistry ,graduate education/research ,hands-on learning/manipulatives ,high school/introductory chemistry ,organic chemistry ,High School/Introductory Chemistry ,First-Year Undergraduate/General ,Organic Chemistry ,Hands-On Learning/Manipulatives ,Combinatorial Chemistry ,Enzymes ,01 natural sciences ,Education ,Educational approach ,Bioorganic chemistry ,010405 organic chemistry ,05 social sciences ,050301 education ,General Chemistry ,Combinatorial synthesis ,Combinatorial chemistry ,0104 chemical sciences ,Enzyme inhibition ,β secretase ,0503 education - Abstract
Multicomponent reactions (MCRs) represent very interesting tools to reach eco-friendly and sustainable transformations in organic chemistry. In particular, the Biginelli reaction furnishes a very easy approach to the synthesis of a library of biological active compounds in an academic course. Here we describe the realization of several experiments involving the synthesis of potential inhibitors of β-secretase by the Biginelli reaction. All of the obtained compounds were tested with a FRET fluorimetric assay. The experiments were proposed to students either at entry level or during advanced laboratory courses of organic and bioorganic chemistry. The learning objectives at the advanced level were to introduce the students to the practice of combinatorial synthesis and to the evaluation of biological activity of combinatorial libraries by enzyme inhibition assays. The meeting of the learning objectives was probed first by analyzing their daily performance in the laboratory and their increasing proactive attitude, and the contents of their final presentations. The resulting marks obtained by the students were compared with the average evaluation of their career. Second, the students were asked to evaluate the course and their own experience, and the outcome of their evaluation was compared with that of the teachers.
- Published
- 2021
20. New Methodology and Framework Information Science-Assisted Analysis of FMO Results for Drug Design
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Tatsuya Takagi
- Subjects
Computer science ,Management science ,Supervised learning ,β secretase ,Unsupervised learning ,Chemistry (relationship) ,Paragraph ,Field (computer science) ,Information science - Abstract
Recently, AI, which is sometimes called ‘Machine Learning’ or ‘Data Mining’, has become common even for public. These techniques are widely utilized even in the field of chemistry and pharmaceutical sciences. However, until very recently, the two fields, AI and theoretical chemistry had been separately developed and utilized for solving chemical or biological problems. In this paragraph, I try to show the recent development of machine learning methods and to show the applications of the methods to the results obtained by theoretical chemistry.
- Published
- 2021
21. MicroRNA-135a and -200b, potential Biomarkers for Alzheimer׳s disease, regulate β secretase and amyloid precursor protein.
- Author
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Liu, Chen-geng, Wang, Jin-ling, Li, Lei, Xue, Li-xiang, Zhang, Yue-qi, and Wang, Pei-chang
- Subjects
- *
MICRORNA , *BIOMARKERS , *ALZHEIMER'S disease , *SECRETASE regulation , *AMYLOID beta-protein precursor , *NEURODEGENERATION , *GENE expression - Abstract
Amyloid precursor protein (APP) and β-site amyloid precursor protein cleaving enzyme (BACE-1) play important roles in the generation of Alzheimer׳s disease (AD), a progressive neurodegenerative disorder. In the present study, microRNA (miR) microarray was used to analyze the miR expression profiles in the hippocampi from APP/PS1 transgenic and wild type mice. The miRs with significant alteration and putative targets on APP or BACE-1 were retrieved (miR-135a, -200b and -429). The deregulations of these miRs were confirmed in mice and further verified in AD patient samples by qPCR. Primary mouse hippocampal neurons, SH-SY5Y and HEK293 cells were used to study the function of miRs on APP and BACE-1. We found that miR-135a, which was downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, directly interacted with the 3′–UTR of BACE-1 and repressed its expression and activity. On the other hand, miR-200b and -429, which were downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, targeted the 3′–UTR of APP and repressed its expression. Furthermore, Aβ42 could downregulate miR-200b expression which may generate a vicious cycle resulted in accumulating Aβ42. The levels of miR-135a and -200b in the serum of DAT group were significantly lower than that of control groups ( P <0.05). The serum miR-200b level of MCI group was higher than that of DAT group ( P <0.05) and lower than that of control group ( P <0.05). We also found decreased miR-135a and -200b levels in the cerebrospinal fluid of DAT group compared with the control group ( P <0.05). In conclusion, these findings showed that miR-135a, -200b and -429 may take part in the progress of AD; miR-200b was of great potential as noninvasive and easily detected blood-based biomarkers of MCI and DAT patients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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22. β-Secretase (BACE1) Inhibitors From Natural Products
- Author
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Atanu Bhattacharjee
- Subjects
Biochemistry ,Chemistry ,β secretase - Published
- 2020
23. Is It the Twilight of BACE1 Inhibitors?
- Author
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Martina Hrabinova, Daniel Jun, Ondrej Soukup, Jaroslav Pejchal, Monika Schmidt, and Tomas Kucera
- Subjects
Amyloid beta ,Skin rashes ,Disease ,Bioinformatics ,Placebo ,Weight loss ,Alzheimer Disease ,Aricle ,mental disorders ,inhibitors ,Medicine ,Aspartic Acid Endopeptidases ,Humans ,β-secretase ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,substrates ,Pharmacology ,clinical trials ,Amyloid beta-Peptides ,biology ,business.industry ,General Medicine ,Clinical trial ,amyloid beta ,Psychiatry and Mental health ,Neurology ,β secretase ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Amyloid Precursor Protein Secretases ,business ,Alzheimer’s disease - Abstract
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.
- Published
- 2020
24. Subcellular dynamics and functional activity of the cleaved intracellular domain of the Na + channel β1 subunit.
- Author
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Haworth AS, Hodges SL, Capatina AL, Isom LL, Baumann CG, and Brackenbury WJ
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Female, Humans, NAV1.7 Voltage-Gated Sodium Channel, Sodium metabolism, Tetrodotoxin pharmacology, Voltage-Gated Sodium Channel beta-1 Subunit genetics, Breast Neoplasms, Sodium Channels metabolism
- Abstract
The voltage-gated Na
+ channel β1 subunit, encoded by SCN1B, regulates cell surface expression and gating of α subunits and participates in cell adhesion. β1 is cleaved by α/β and γ-secretases, releasing an extracellular domain and intracellular domain (ICD), respectively. Abnormal SCN1B expression/function is linked to pathologies including epilepsy, cardiac arrhythmia, and cancer. In this study, we sought to determine the effect of secretase cleavage on β1 function in breast cancer cells. Using a series of GFP-tagged β1 constructs, we show that β1-GFP is mainly retained intracellularly, particularly in the endoplasmic reticulum and endolysosomal pathway, and accumulates in the nucleus. Reduction in endosomal β1-GFP levels occurred following γ-secretase inhibition, implicating endosomes and/or the preceding plasma membrane as important sites for secretase processing. Using live-cell imaging, we also report β1ICD-GFP accumulation in the nucleus. Furthermore, β1-GFP and β1ICD-GFP both increased Na+ current, whereas β1STOP-GFP, which lacks the ICD, did not, thus highlighting that the β1-ICD is necessary and sufficient to increase Na+ current measured at the plasma membrane. Importantly, although the endogenous Na+ current expressed in MDA-MB-231 cells is tetrodotoxin (TTX)-resistant (carried by Nav 1.5), the Na+ current increased by β1-GFP or β1ICD-GFP was TTX-sensitive. Finally, we found β1-GFP increased mRNA levels of the TTX-sensitive α subunits SCN1A/Nav 1.1 and SCN9A/Nav 1.7. Taken together, this work suggests that the β1-ICD is a critical regulator of α subunit function in cancer cells. Our data further highlight that γ-secretase may play a key role in regulating β1 function in breast cancer., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
25. Synthesis of a 6-CF3-Substituted 2-Amino-dihydro-1,3-thiazine β-Secretase Inhibitor by N,N-Diethylaminosulfur Trifluoride-Mediated Chemoselective Cyclization
- Author
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Masayoshi Ogawa, Shinji Suzuki, Kosuke Anan, Ken-ichi Kusakabe, Akihiro Takada, Shinya Hisakawa, and Takuya Oguma
- Subjects
010405 organic chemistry ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Diethylaminosulfur trifluoride ,chemistry.chemical_compound ,Trifluoride ,Thiourea ,chemistry ,Thiazine ,Yield (chemistry) ,β secretase ,Chemoselectivity - Abstract
The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N,N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine β-secretase inhibitor 2.
- Published
- 2018
26. Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate
- Author
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Sergio A. Alonso de Diego, Daniel Oehlrich, Harrie J.M. Gijsen, Andrés A. Trabanco, Hana Prokopcová, Nigel Austin, Michel Surkyn, Dries Van den Bossche, Frederik J. R. Rombouts, Deborah Dhuyvetter, Gregor James Macdonald, Sven Franciscus Anna Van Brandt, Herman Borghys, Michiel Van Gool, Diederik Moechars, Aránzazu García-Molina, Michel Anna Jozef De Cleyn, and Carolina Martinez-Lamenca
- Subjects
Male ,0301 basic medicine ,ERG1 Potassium Channel ,Guinea Pigs ,hERG ,Drug Evaluation, Preclinical ,Administration, Oral ,Biological Availability ,Mice, Inbred Strains ,Pharmacology ,Rats, Sprague-Dawley ,Amidine ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Drug Stability ,In vivo ,Oxazines ,Drug Discovery ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Structure–activity relationship ,Protease Inhibitors ,Amyloid beta-Peptides ,Cardiovascular safety ,biology ,Peptide Fragments ,Clinical trial ,030104 developmental biology ,chemistry ,Cardiovascular Diseases ,Toxicity ,β secretase ,biology.protein ,Molecular Medicine ,Administration, Intravenous ,Amyloid Precursor Protein Secretases ,Chemical and Drug Induced Liver Injury ,030217 neurology & neurosurgery - Abstract
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the pKa of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.
- Published
- 2018
27. β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics
- Author
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Tahir S Pillay and Ataul Islam
- Subjects
0301 basic medicine ,Pharmacoinformatics ,Quantitative Structure-Activity Relationship ,Computational biology ,Molecular Dynamics Simulation ,01 natural sciences ,03 medical and health sciences ,Alzheimer Disease ,Structural Biology ,Drug Discovery ,mental disorders ,Amyloid precursor protein ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Virtual screening ,Molecular Structure ,biology ,Chemistry ,Reproducibility of Results ,General Medicine ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,ROC Curve ,biology.protein ,β secretase ,Identification (biology) ,Amyloid Precursor Protein Secretases ,Pharmacophore ,Algorithms - Abstract
In this study we searched for potential β-site amyloid precursor protein cleaving enzyme1 (BACE1) inhibitors using pharmacoinformatics. A large dataset containing 7155 known BACE1 inhibitors was evaluated for pharmacophore model generation. The final model (R = 0.950, RMSD = 1.094, Q
- Published
- 2018
28. Modulation of γ- and β-Secretases as Early Prevention Against Alzheimer’s Disease
- Author
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Bart De Strooper, Lucía Chávez-Gutiérrez, and Iryna Voytyuk
- Subjects
0301 basic medicine ,Amyloid beta-Peptides ,biology ,Amyloid β ,Disease ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,Alzheimer Disease ,medicine ,biology.protein ,β secretase ,Animals ,Humans ,Dementia ,γ secretase ,Amyloid Precursor Protein Secretases ,Psychology ,Neuroscience ,Amyloid precursor protein secretase ,Biological Psychiatry - Abstract
The genetic evidence implicating amyloid-β in the initial stage of Alzheimer's disease is unequivocal. However, the long biochemical and cellular prodromal phases of the disease suggest that dementia is the result of a series of molecular and cellular cascades whose nature and connections remain unknown. Therefore, it is unlikely that treatments directed at amyloid-β will have major clinical effects in the later stages of the disease. We discuss the two major candidate therapeutic targets to lower amyloid-β in a preventive mode, i.e., γ- and β-secretase; the rationale behind these two targets; and the current state of the field.
- Published
- 2018
29. β-secretase inhibitors for Alzheimer's disease: heading in the wrong direction?
- Author
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Dennis J. Selkoe
- Subjects
Heading (navigation) ,Thiadiazines ,business.industry ,Treatment outcome ,Disease ,Bioinformatics ,Cyclic S-Oxides ,Neuroprotective Agents ,Treatment Outcome ,Alzheimer Disease ,β secretase ,Humans ,Medicine ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,Enzyme Inhibitors ,Wrong direction ,business - Published
- 2019
30. Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing
- Author
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Rebecca E. K. MacPherson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Physiology ,Review ,Disease ,Amyloid beta-Protein Precursor ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Alzheimer Disease ,Risk Factors ,β amyloid ,Physiology (medical) ,Internal medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Obesity ,Significant risk ,Exercise ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,Brain ,medicine.disease ,030104 developmental biology ,Endocrinology ,β secretase ,biology.protein ,Amyloid Precursor Protein Secretases ,Insulin Resistance ,Sedentary Behavior ,business ,Risk Reduction Behavior ,030217 neurology & neurosurgery - Abstract
Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer’s disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.
- Published
- 2017
31. In Silico Analysis Towards Exploring Potential β Secretase 1 (BACE1) Inhibitors; The Cause of Alzhemier Disease
- Author
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Fina Aryani, Neni Frimayanti, Nina Rishanti, and Marzieh Yaeghoobi
- Subjects
History ,Chemistry ,In silico ,β secretase ,Disease ,Pharmacology ,Computer Science Applications ,Education - Abstract
1,5 benzothiazepine chalcone derivative compounds were used as ligands and docked with protein target 2XFJ code from Hydrolase enzyme crystallographic structure. Molecular Operating Environment 2020.0901 (MOE) computer program was used as software to perform docking. The aim of this research is to determine the potentiality of 1,5 benzothiazepines as β secretase 1 (BACE1) inhibitors using molecular docking studies and also to predict their toxicity using SwissADME. Based on the docking results, some promising interactions were observed between 1,5 benzothiazepines and β secretase 1 (BACE1) receptors using Verubecestat as a positive control. Compounds MA2, MA4 and MA10 shown to have the potentiality as active inhibitors for the β secretase 1 (BACE1). These three compounds have binding free energy values of -4,6302 kcal/mol, -4,4268 kcal/mol, and -5,3427 kcal/mol, respectively. In addition, they also exhibited factor of binding (i. e. a measure of the probability of tested compounds to bind with the same amino acid that the positive control, Verubecestat). The predicted toxicity for these three compounds were measured using SwissADME and the results showed that MA2, MA4 and MA10 are not toxic and they can be used as reference for designing new inhibitors for β secretase 1 (BACE1).
- Published
- 2021
32. Regulation of β cleavage of amyloid precursor protein.
- Author
-
Wang, Jun-Feng, Lu, Rui, and Wang, Yi-Zheng
- Abstract
Copyright of Neuroscience Bulletin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2010
- Full Text
- View/download PDF
33. Cerebrospinal Fluid and Serum Beta Secretase Activities in Alzheimer's Disease.
- Author
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Yaka, Erdem, Genç, Şermin, İyılıkçı, Leyla, and Yener, Görsev
- Subjects
- *
CEREBROSPINAL fluid , *ALZHEIMER'S patients , *BIOMARKERS , *SERUM , *NEUROLOGICAL research - Abstract
Objective: In this study, we aimed to investigate β secretase activities in cerebrospinal fluid (CSF) and serum of patients with Alzheimer's disease (AD) as a possible biological marker in AD. Methods: The serum and the CSF samples were investigated in both patient and control groups. For serum analysis, thirteen patients diagnosed with 'probable AD' according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV) and National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders (NINCDS/ADRDA) criteria and twelve controls were studied. For CSF analysis twelve patients diagnosed with 'probable AD' according to DSM IV and NINCDS/ADRDA criteria and nine controls were studied. Results: There was no statistical difference in CSF β secretase activity between AD patients (mean±S.E., 343.8 ± 47.9) and the controls (mean±S.E., 409.6 ± 34.9). There was also no statistical difference in serum β secretase activity between the patients (mean±S.E., 2298.9 ± 70.3) and the controls (mean±S.E., 2438.2 ± 119.4). Conclusions: In conclusion, these results indicate that beta-secretase activity is not changed in Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2010
34. Synthesis of β-Secretase Inhibitor NB-360
- Author
-
Philip Kocienski
- Subjects
Stereochemistry ,Chemistry ,β secretase - Published
- 2021
35. A microfluidics-based mobility shift assay to identify new inhibitors of β-secretase for Alzheimer’s disease
- Author
-
Junwei Meng, Yu-Chih Liu, Xuehong Zhang, Rongfeng Liu, and Haiyan Zhu
- Subjects
0301 basic medicine ,Mutant ,Microfluidics ,Drug Evaluation, Preclinical ,Electrophoretic Mobility Shift Assay ,Peptide ,Biochemistry ,Analytical Chemistry ,Peptide substrate ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,mental disorders ,Aspartic Acid Endopeptidases ,Humans ,Electrophoretic mobility shift assay ,IC50 ,Enzyme Assays ,chemistry.chemical_classification ,Microfluidic Analytical Techniques ,Molecular biology ,Fluorescence ,Recombinant Proteins ,Kinetics ,030104 developmental biology ,chemistry ,β secretase ,Amyloid Precursor Protein Secretases ,030217 neurology & neurosurgery - Abstract
The β-secretase (BACE1) initiates the generation of toxic amyloid-β peptide (Aβ) from amyloid-β precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer’s disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification. To validate the assay, the inhibition and kinetic parameter values of two known inhibitors (AZD3839 and AZD3293) were evaluated, and the results were in good agreement with those reported by other methods. Finally, the assay was applied to screen for new inhibitors from a 900-compound library in a 384-well format, and one novel hit (IC50 = 26.5 ± 1.5 μM) was identified. Compared with the common fluorescence-based assays, the primary advantage of the direct MMSA was to discover novel BACE1 inhibitors with lower auto-fluorescence interference, and its superb capability for kinetic study.
- Published
- 2017
36. New aromatic compounds from the rhizomes of Homalomena occulta
- Author
-
Jing Ye, Peng Yin, and Mei-Tian Xiao
- Subjects
010405 organic chemistry ,Stereochemistry ,Chemistry ,Plant Science ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Rhizome ,010404 medicinal & biomolecular chemistry ,Ic50 values ,β secretase ,Homalomena occulta ,Agronomy and Crop Science ,Biotechnology - Abstract
Three new aromatic compounds, identified as 1-(3′,4′-methylenedioxy-phenyl)-10-(3″-hydroxyphenyl)-decane (1), 1-(3′,4′-methylenedioxy-phenyl)-12-(3″-hydroxyphenyl)-dodecane (2), and 1-(3′,4′-methylenedioxy-phenyl)-12-(3″-hydroxyphenyl)-6Z-dodecylene (3), along with six known compounds (4–9) were isolated from the 95% EtOH extract of Homalomena occulta. Their structures were elucidated by chemical and spectral methods Compounds 4–9 were isolated for the first time from this plant. Compounds 1–3 exhibited inhibitory activity against BACE1, with IC50 values of 0.82–1.09 μmol/L.
- Published
- 2017
37. Association of β-Secretase Functional Polymorphism with Risk of Schizophrenia
- Author
-
GholipourFatemeh, DarvishHossein, MovafaghAbolfazl, MirfakhraieReza, OhadiMina, TayebiGouya, MansooriNader, Rahimi-AliabadiSimin, NejadFarhad Ramezani, DivsalarShahram, JamshidiJavad, ShahmohammadibeniNeda, MoudiSusan, TaheriMohammad, and ShandizEhsan Esmaili
- Subjects
Adult ,Male ,0301 basic medicine ,Receptor, ErbB-4 ,Iran ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,mental disorders ,Aspartic Acid Endopeptidases ,Humans ,Genetic Predisposition to Disease ,Neurotransmitter ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,ERBB4 ,Functional polymorphism ,Genetics ,General Medicine ,Middle Aged ,030104 developmental biology ,Haplotypes ,chemistry ,Case-Control Studies ,Schizophrenia ,β secretase ,Female ,Amyloid Precursor Protein Secretases ,Signal transduction ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is β-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population.A total of 973 subjects, including 480 SZ patients and 493 healthy controls, matched by ethnicity, age, and gender, were recruited in a case-control study. Genomic DNA was extracted from peripheral blood of all subjects and genotyping of rs707284 and rs490460 was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra-primer amplification refractory mutation system (tetra-ARMS) PCR genotyping assays, respectively.A significant association was observed between the rs490460 T allele and SZ (p = 0.0002, odds ratio 0.69, 95% confidence interval 0.57-0.84). There was no association between the risk of SZ and rs707284.Our data indicate that rs490460 is associated with the risk of SZ. In silico analysis indicates that rs490460 may be a potential splicing site, which affects protein structure. Replication studies are needed to confirm our data.
- Published
- 2017
38. Fast pulling of ligand approach for the design of β-secretase 1 inhibitors
- Author
-
Van V. Vu, Minh Tung Nguyen, Son Tung Ngo, and Duc Toan Truong
- Subjects
010304 chemical physics ,Chemistry ,General Physics and Astronomy ,Interaction energy ,010402 general chemistry ,Ligand (biochemistry) ,01 natural sciences ,0104 chemical sciences ,Crystallography ,symbols.namesake ,Computational chemistry ,mental disorders ,0103 physical sciences ,β secretase ,symbols ,Physical and Theoretical Chemistry ,van der Waals force ,Electrostatic interaction - Abstract
The fast pulling of ligand (FPL) method, which evaluates the relative ligand-protein binding affinity with low CPU usage and high accuracy, was applied for the first time to determine the affinity of β-secretase 1 (BACE1) and its inhibitors using steered-molecular dynamics simulations. The total non-bonded interaction energy difference Δ E total is a highly appropriate criterion to predict the relative BACE1-inhibitor binding affinity with strong correlation to experimental data ( R = 0.92 ) and small deviation ( δ E total = 7 % ). The van der Waals interaction and electrostatic interaction contribute 56% and 44% to the total non-bonded interaction energy between BACE1 and its inhibitors.
- Published
- 2017
39. Capsicum annuum var. grossum (Bell Pepper) Inhibits β-Secretase Activity and β-Amyloid1–40 Aggregation
- Author
-
Sabina Passamonti, Omodesola O. Ogunruku, Ganiyu Oboh, Federica Tramer, Aline Augusti Boligon, Ogunruku, O. O., Oboh, G., Passamonti, S., Trammer, F., and Boligon, A. A.
- Subjects
0301 basic medicine ,Amyloid beta-Peptide ,Amyloid ,Medicine (miscellaneous) ,1-40 ,Plant Extract ,Protein Aggregates ,03 medical and health sciences ,0302 clinical medicine ,Peptide Fragment ,Alzheimer Disease ,Pepper ,Amyloid precursor protein ,medicine ,Alzheimer's disease ,bell pepper ,Capsicum spp ,neurodegeneration ,β-amyloid ,β-secretase ,Amyloid Precursor Protein Secretases ,Amyloid beta-Peptides ,Capsicum ,Enzyme Inhibitors ,Humans ,Kinetics ,Peptide Fragments ,Plant Extracts ,Enzyme Inhibitor ,Amyloid Precursor Protein Secretase ,Senile plaques ,Kinetic ,Nutrition and Dietetics ,biology ,Chemistry ,Neurodegeneration ,food and beverages ,medicine.disease ,In vitro ,030104 developmental biology ,Biochemistry ,β secretase ,biology.protein ,Amyloid precursor protein secretase ,030217 neurology & neurosurgery ,Human - Abstract
The deposition of amyloid protein as senile plaques is the major signature of Alzheimer's disease (AD). It is produced by the sequential cleavage of the amyloid precursor protein by secretases. Moreover, peppers are noted for their antiaging and cognitive enhancing properties. Thus, in this study, the effects of polyphenol-rich extracts from bell pepper on amyloid production and aggregation in vitro were investigated. Bell pepper (ripe and unripe) was extracted with methanol-1 N HCl (1:1 v/v). Thereafter, the inhibitory potentials of the extracts on β-secretase and β-amyloid1-40 aggregation were determined. Phenolic composition of the pepper fruits was further determined by HPLC-DAD (high performance liquid chromatography-diode array detector). There was a dose-dependent inhibition of β-secretase by the pepper fruits with the ripe fruits (2.17 ± 0.17 μg/L) showing a significantly (P < .05) higher inhibitory effect than the unripe (3.44 ± 0.11 μg/L). Furthermore, Thioflavin-T and transmission electron microscopy analyses revealed that phenolic extracts from pepper fruits (1 and 10 μg/L) could counteract the initial aggregation of Aβ1-40, as well as prevent further aggregation preformed fibrils. These inhibitory activities could be attributed to the predominant presence of phenolic constituents in the pepper fruits. It is possible to conclude that bell pepper could be a possible dietary intervention into the management of AD.
- Published
- 2017
40. β-secretase inhibitors from sesame seeds and turmeric rhizomes
- Author
-
N Zaima, M Morimoto, K Murata, Shinichi Matsumura, Yuri Yoshioka, and Hideaki Matsuda
- Subjects
Pharmacology ,Complementary and alternative medicine ,Traditional medicine ,Organic Chemistry ,Drug Discovery ,β secretase ,Pharmaceutical Science ,Molecular Medicine ,Analytical Chemistry ,Rhizome - Published
- 2016
41. Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose
- Author
-
Yasuyoshi Iso, Naoki Kanegawa, Vijay Urmaliya, Kazuki Fujimoto, Kazuo Komano, Ard Teisman, An Van Den Bergh, Herman Borghys, Hisanori Ito, Shuhei Yoshida, Shigeru Ando, Yasuto Kido, Nigel E. Austin, Naoya Asada, Shinji Suzuki, Kenji Nakahara, Ken-ichi Kusakabe, Eriko Matsuoka, Harrie J.M. Gijsen, Gaku Sakaguchi, Genta Tadano, Yoshinori Yamano, Tamio Fukushima, Takahiko Yamamoto, Deborah Dhuyvetter, and Kouki Fuchino
- Subjects
Male ,Liver toxicity ,Drug Evaluation, Preclinical ,Thiazines ,Pharmacology ,01 natural sciences ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Dogs ,In vivo ,Thiazine ,Alzheimer Disease ,mental disorders ,Drug Discovery ,Amyloid precursor protein ,Animals ,Humans ,Protease Inhibitors ,Volume concentration ,030304 developmental biology ,Cytochrome P-450 CYP2C9 ,0303 health sciences ,Amyloid beta-Peptides ,biology ,Half-life ,Brain ,Heart ,Haplorhini ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,chemistry ,Liver ,biology.protein ,β secretase ,Molecular Medicine ,Trough level ,Female ,Amyloid Precursor Protein Secretases ,Half-Life - Abstract
Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aβ reduction of 80% at trough level.
- Published
- 2019
42. Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads
- Author
-
Sven Franciscus Anna Van Brandt, Aldo Peschiulli, Andrés A. Trabanco, Ann Vos, Nigel Austin, Sergio A. Alonso de Diego, Michel Anna Jozef De Cleyn, Hana Prokopcová, Michel Surkyn, Dieder Moechars, Daniel Oehlrich, Gregor James Macdonald, Frederik J. R. Rombouts, Juan Antonio Vega, Michiel Van Gool, Ana Isabel de Lucas, Harrie J.M. Gijsen, and Gary Tresadern
- Subjects
010405 organic chemistry ,Organic Chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Amidine ,Enzyme binding ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Piperazine ,chemistry ,Drug Discovery ,β secretase ,Efflux ,IC50 - Abstract
[Image: see text] Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer’s disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC(50) ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.
- Published
- 2019
43. Lowering of Amyloid-Beta by β-Secretase Inhibitors - Some Informative Failures
- Author
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David S. Knopman
- Subjects
biology ,Thiadiazines ,Amyloid beta ,business.industry ,General Medicine ,030204 cardiovascular system & hematology ,Pharmacology ,Cyclic S-Oxides ,medicine.disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,biology.protein ,β secretase ,medicine ,Humans ,030212 general & internal medicine ,Alzheimer's disease ,Amyloid Precursor Protein Secretases ,business ,Amyloid precursor protein secretase - Abstract
BACKGROUND: Prodromal Alzheimer’s disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer’s disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P=0.67 for the comparison between the 12-mg group and the placebo group and P=0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer’s disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer’s disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, .)
- Published
- 2019
44. BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis
- Author
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Zhe Wang, Yili Wu, Weihong Song, Qin Xu, Xi Liu, and Fang Cai
- Subjects
0301 basic medicine ,biology ,Clusterin ,Chemistry ,General Medicine ,Neuropathology ,Disease pathogenesis ,3. Good health ,Cell biology ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,mental disorders ,Amyloid precursor protein ,biology.protein ,β secretase ,Senile plaques ,Research Article - Abstract
Deposition of amyloid-β protein (Aβ) to form neuritic plaques is the characteristic neuropathology of Alzheimer’s disease (AD). Aβ is generated from amyloid precursor protein (APP) by β- and γ-secretase cleavages. BACE1 is the β-secretase and its inhibition induces severe side effects, whereas its homolog BACE2 normally suppresses Aβ by cleaving APP/Aβ at the θ-site (Phe(20)) within the Aβ domain. Here, we report that BACE2 also processes APP at the β site, and the juxtamembrane helix (JH) of APP inhibits its β-secretase activity, enabling BACE2 to cleave nascent APP and aggravate AD symptoms. JH-disrupting mutations and clusterin binding to JH triggered BACE2-mediated β-cleavage. Both BACE2 and clusterin were elevated in aged mouse brains, and enhanced β-cleavage during aging. Therefore, BACE2 contributes to AD pathogenesis as a conditional β-secretase and could be a preventive and therapeutic target for AD without the side effects of BACE1 inhibition.
- Published
- 2019
45. Inhibitory Activities of Sesame Seed Extract and its Constituents against β-Secretase
- Author
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Nobuhiro Zaima, Shinichi Matsumura, Masahiro Iwaki, Hideaki Matsuda, Yuri Yoshioka, Kazuya Murata, and Masanori Morimoto
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Plant Science ,Inhibitory postsynaptic potential ,01 natural sciences ,Sesamum ,chemistry.chemical_compound ,Oral administration ,Sesamin ,Drug Discovery ,Sesamolin ,Pharmacology ,biology ,Traditional medicine ,010405 organic chemistry ,Chemistry ,Plant Extracts ,food and beverages ,General Medicine ,biology.organism_classification ,Sesame seed ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Sesame seed extract ,Butyrylcholinesterase ,Seeds ,β secretase ,Acetylcholinesterase ,Cholinesterase Inhibitors ,Amyloid Precursor Protein Secretases - Abstract
The need for a preventive agent against dementia led us to screen natural plant resources. Among the herbs and spices tested, sesame seed prepared from Sesamum indicum seeds showed potent β-secretase inhibitory activity. The active principles were determined to be sesamin and sesamolin, typical lignans in S. indicum. The IC50 values of sesamin and sesamolin were 257 and 140 μM, respectively. These compounds were investigated in a preliminary absorption experiment. After oral administration, these compounds were detected in an intact form in the brain and serum. These results suggest that consumption of sesame seeds may prevent dementia by sesamin and sesamolin, the constituents in sesame seeds.
- Published
- 2018
46. Tricyclic Inhibitors of β-Secretase and Their Methods of Use for the Treatment of Alzheimer's Disease
- Author
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Benjamin E. Blass
- Subjects
chemistry.chemical_classification ,Text mining ,chemistry ,business.industry ,Organic Chemistry ,Drug Discovery ,β secretase ,Medicine ,Disease ,Pharmacology ,business ,Biochemistry ,Tricyclic - Published
- 2018
47. Development of Novel FRET Substrate for the Evaluation of β-Secretase (BACE1) and Its Application
- Author
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Yasuhiro Iida and Zhi Ling Lui
- Subjects
Förster resonance energy transfer ,Chemistry ,Biophysics ,β secretase ,Substrate (chemistry) - Abstract
A neuropathological diagnosis of Alzheimer's disease (AD) relies on the detection of amyloid plaques, clumps of beta-amyloid made up of insoluble fibrils. Sequential cleavage by β-secretase (BACE) and γ-secretase produces the amyloid-β peptide fragment, which then aggregates into the clumps of amyloid plaques. As the β-secretase activity is specifically high in AD patient, the enzyme is regarded as the primary target of anti-AD reagent. All the conventional β-secretase inhibitors are substrate analogs, which means those inhibitors are competitive and reversible inhibitors. Therefore, a non-competitive enzyme inhibitor of β-secretase might be a perfect inhibitor for AD. To search for non-competitive enzyme inhibitor of β-secretase, we developed new method to evaluate non-competitive enzyme inhibitors easily by using flow injection analysis (FIA) in combination with immobilized enzyme. In general, FRET substrates linked by recognition sequence of β-secretase are used to evaluate the β-secretase activity. In this study, we constructed a novel FRET substrate which is made up of ECFP as the donor, and EYFP as the acceptor. These proteins are then linked with β-secretase recognition sequence with 8 amino acids. ECFP transfers its excitation energy to EYFP, causing EYFP to emit its characteristic fluorescence. By observing the wavelength using spectrophotometer, we can judge if the material or herbs have the ability to be the inhibitor of β-secretase. Therefore, both the FRET substrates and β-secretase we constructed can be produce with a large amount by using E. coli. And because the protein of FRET substrates and BACE1 can be obtained easily with the E. coli we constructed, therefore we will be able to search for the inhibitors of β-secretase by the FIA screening method with low cost.
- Published
- 2020
48. Computational Modeling of β-Secretase 1 (BACE-1) Inhibitors Using Ligand Based Approaches
- Author
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Vijay S. Pande, Govindan Subramanian, Bharath Ramsundar, and Rajiah Aldrin Denny
- Subjects
Models, Molecular ,0301 basic medicine ,Quantitative structure–activity relationship ,General Chemical Engineering ,In silico ,Quantitative Structure-Activity Relationship ,Computational biology ,Library and Information Sciences ,Ligands ,010402 general chemistry ,Molecular Fingerprint ,01 natural sciences ,Machine Learning ,Small Molecule Libraries ,03 medical and health sciences ,Computational chemistry ,Drug Discovery ,Aspartic Acid Endopeptidases ,Humans ,Computer Simulation ,Artificial neural network ,Chemistry ,General Chemistry ,Ligand (biochemistry) ,Affinities ,Chemical space ,0104 chemical sciences ,Computer Science Applications ,030104 developmental biology ,β secretase ,Neural Networks, Computer ,Amyloid Precursor Protein Secretases - Abstract
The binding affinities (IC50) reported for diverse structural and chemical classes of human β-secretase 1 (BACE-1) inhibitors in literature were modeled using multiple in silico ligand based modeling approaches and statistical techniques. The descriptor space encompasses simple binary molecular fingerprint, one- and two-dimensional constitutional, physicochemical, and topological descriptors, and sophisticated three-dimensional molecular fields that require appropriate structural alignments of varied chemical scaffolds in one universal chemical space. The affinities were modeled using qualitative classification or quantitative regression schemes involving linear, nonlinear, and deep neural network (DNN) machine-learning methods used in the scientific literature for quantitative–structure activity relationships (QSAR). In a departure from tradition, ∼20% of the chemically diverse data set (205 compounds) was used to train the model with the remaining ∼80% of the structural and chemical analogs used as part...
- Published
- 2016
49. Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies
- Author
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Dima A. Sabbah and Haizhen A. Zhong
- Subjects
0301 basic medicine ,Stereochemistry ,Static Electricity ,Protonation ,Peptide ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,03 medical and health sciences ,Molecular dynamics ,0302 clinical medicine ,mental disorders ,Materials Chemistry ,Protease Inhibitors ,Physical and Theoretical Chemistry ,Binding site ,Spectroscopy ,chemistry.chemical_classification ,Binding Sites ,Chemistry ,Hydrogen bond ,Computer Graphics and Computer-Aided Design ,Molecular Docking Simulation ,030104 developmental biology ,Searching the conformational space for docking ,Docking (molecular) ,β secretase ,Amyloid Precursor Protein Secretases ,Protons ,030217 neurology & neurosurgery - Abstract
β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is -1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.
- Published
- 2016
50. Discovery of polymethoxyflavones from black ginger (Kaempferia parviflora) as potential β-secretase (BACE1) inhibitors
- Author
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Jinhyuk Lee, Chi-Tang Ho, Mira Jun, and Kumju Youn
- Subjects
0301 basic medicine ,ved/biology.organism_classification_rank.species ,Medicine (miscellaneous) ,Cleavage (embryo) ,Docking ,03 medical and health sciences ,mental disorders ,Amyloid precursor protein ,TX341-641 ,chemistry.chemical_classification ,Kaempferia parviflora ,Serine protease ,Nutrition and Dietetics ,biology ,β-secretase (BACE1) ,ved/biology ,Nutrition. Foods and food supply ,β-amyloid peptide (Aβ) ,Alzheimer's disease ,Inhibitory potency ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,Polymethoxyflavone ,Docking (molecular) ,β secretase ,biology.protein ,Food Science - Abstract
Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has emerged as a prime target in Alzheimer's disease research because BACE1 is the rate-limiting enzyme involved in the abnormal production of β-amyloid peptides. In the course of exploring natural BACE1 inhibitors, the present study focused on the major polymethoxyflavones from Kaempferia parviflora: 5,7-dimethoxyflavone (DMF), 5,7,4′-trimethoxyflavone (TMF), and 3,5,7,3′,4′-pentamethoxyflavone (PMF). All polymethoxyflavones exhibited strong BACE1 inhibitory potency, with no significant suppression of α-secretase or other serine protease activities, indicating that they were relatively specific and selective BACE1 inhibitors. Dixon and Lineweaver–Burk plots indicated that they produced non-competitive inhibition of substrate cleavage. An in silico docking study of human BACE1 with polymethoxyflavones demonstrated the binding energy and the interacting residues. Our findings indicated that Kaempferia parviflora could provide a novel therapy for the prevention of Alzheimer's disease and provide a scaffold for exploration of more potent natural BACE1 inhibitors.
- Published
- 2016
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