scholarly journals Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

2021 ◽  
Author(s):  
James D. Grayson ◽  
Matthew P. Baumgartner ◽  
Cleide Dos Santos Souza ◽  
Samuel J. Dawes ◽  
Imane Ghafir El Idrissi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Virtual Screening ◽  
Effective Strategy ◽  
New Approach ◽  
Biochemical Assays ◽  
Std Nmr

A new approach combining virtual screening, 19F and STD NMR, and biochemical assays using hiPSC and targetting multiple pathways involving Aβ, PrPC and Tau provides a more effective strategy for Alzheimer's disease drug discovery than Aβ only approach.

scholarly journals Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer’s disease model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lishu Duan ◽  
Mufeng Hu ◽  
Joseph A. Tamm ◽  
Yelena Y. Grinberg ◽  
Fang Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Disease Model ◽  
Mitochondrial Morphology ◽  
Individual Gene ◽  
Human Genes ◽  
Future Drug ◽  
Tau Aggregation

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

scholarly journals Potential Cancer- and Alzheimer’s Disease-Targeting Phosphodiesterase Inhibitors from Uvaria alba: Insights from In Vitro and Consensus Virtual Screening

ACS Omega ◽  
2021 ◽  
Vol 6 (12) ◽  
pp. 8403-8417
Author(s):  
Mark Tristan Quimque ◽  
Kin Israel Notarte ◽  
Arianne Letada ◽  
Rey Arturo Fernandez ◽  
Delfin Yñigo Pilapil ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Phosphodiesterase Inhibitors ◽  
Potential Cancer

scholarly journals Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1946
Author(s):  
Nitin Chitranshi ◽  
Ashutosh Kumar ◽  
Samran Sheriff ◽  
Veer Gupta ◽  
Angela Godinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Virtual Screening ◽  
Cathepsin B ◽  
Amyloid Β ◽  
Proteolytic Degradation ◽  
Hydrogen Bond Acceptor ◽  
Starting Point ◽  
The Brain

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

scholarly journals Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease

2021 ◽  
Author(s):  
Michele Rossi ◽  
Michela Freschi ◽  
Luciana de Camargo Nascente ◽  
Alessandra Salerno ◽  
Sarah de Melo Viana Teixeira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery

Challenges in Alzheimer's Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data

2020 ◽  
Vol 107 (4) ◽  
pp. 796-805 ◽  
Author(s):  
Daniela J. Conrado ◽  
Sridhar Duvvuri ◽  
Hugo Geerts ◽  
Jackson Burton ◽  
Carla Biesdorf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Open Data ◽  
Drug Discovery And Development ◽  
Modeling Simulation

scholarly journals Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies

2009 ◽  
Vol 8 (10) ◽  
pp. 783-793 ◽  
Author(s):  
Kurt R. Brunden ◽  
John Q. Trojanowski ◽  
Virginia M.-Y. Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery

A new approach for Alzheimer's disease treatment through P-gp regulation via ibuprofen

2018 ◽  
Vol 214 (11) ◽  
pp. 1765-1771 ◽  
Author(s):  
Chengxiang Zhang ◽  
Heng Qin ◽  
Rui Zheng ◽  
Yubang Wang ◽  
Ting Yan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Treatment ◽  
New Approach

scholarly journals Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer’s disease

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Sidra Khalid ◽  
Muhammad Ammar Zahid ◽  
Hussain Ali ◽  
Yeong S. Kim ◽  
Salman Khan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Neuroprotective Effects
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