Abstract
The aggregation of tau protein into paired helical filaments is one of the hallmarks of Alzheimers disease and related dementias. We therefore continue our search for non-toxic, cell penetrating inhibitors of tau aggregation, which hold potential for brain penetration. Pickhardt et al. (2005) have reported a high throughput screen for tau aggregation inhibitors previously, which resulted in the identification of several hit classes. Here we report the identification of novel inhibitors which were not present in the initial high throughput assay. This was achieved by transformation of the high throughput screen data into the 3D relationships of virtual pharmacophores The pharmacophore models were utilized in a virtual screen of a Maybridge database. The virtual screen provided 136 hits; 19 representative hits were selected and assayed, this resulted in two novel leads with an IC50 < 13 μM. These two leads feature a novel scaffold for tau aggregation inhibitors.
Keywords: Alzheimer's disease, inhibitors, molecular modeling, protein aggregation, tau protein
Current Alzheimer Research
Title: Screening for Inhibitors of Tau Protein Aggregation into Alzheimer Paired Helical Filaments: A Ligand Based Approach Results in Successful Scaffold Hopping
Volume: 4 Issue: 3
Author(s): Gregor Larbig, Marcus Pickhardt, David G. Lloyd, Boris Schmidt and Eckhard Mandelkow
Affiliation:
Keywords: Alzheimer's disease, inhibitors, molecular modeling, protein aggregation, tau protein
Abstract: The aggregation of tau protein into paired helical filaments is one of the hallmarks of Alzheimers disease and related dementias. We therefore continue our search for non-toxic, cell penetrating inhibitors of tau aggregation, which hold potential for brain penetration. Pickhardt et al. (2005) have reported a high throughput screen for tau aggregation inhibitors previously, which resulted in the identification of several hit classes. Here we report the identification of novel inhibitors which were not present in the initial high throughput assay. This was achieved by transformation of the high throughput screen data into the 3D relationships of virtual pharmacophores The pharmacophore models were utilized in a virtual screen of a Maybridge database. The virtual screen provided 136 hits; 19 representative hits were selected and assayed, this resulted in two novel leads with an IC50 < 13 μM. These two leads feature a novel scaffold for tau aggregation inhibitors.
Export Options
About this article
Cite this article as:
Gregor Larbig , Marcus Pickhardt , David G. Lloyd , Boris Schmidt and Eckhard Mandelkow , Screening for Inhibitors of Tau Protein Aggregation into Alzheimer Paired Helical Filaments: A Ligand Based Approach Results in Successful Scaffold Hopping, Current Alzheimer Research 2007; 4 (3) . https://dx.doi.org/10.2174/156720507781077250
DOI https://dx.doi.org/10.2174/156720507781077250 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Development of Nucleic Acid Drugs for Neurological Disorders
Current Topics in Medicinal Chemistry An Optimal Approach for Selecting Discriminant Regions for the Diagnosis of Alzheimer's Disease
Current Alzheimer Research Recent Patents on Polymeric Scaffolds for Tissue Engineering
Recent Patents on Biomedical Engineering (Discontinued) Genetic Engineering of AAV Capsid Gene for Gene Therapy Application
Current Gene Therapy BDNF Serum Concentrations Show No Relationship with Diagnostic Group or Medication Status in Neurodegenerative Disease
Current Alzheimer Research Antiangiogenic Function of Antithrombin is Dependent on its Conformational Variation: Implication for Other Serpins
Protein & Peptide Letters Strength and Weaknesses of Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease and Possible Detection of Overlaps with Frailty Process
CNS & Neurological Disorders - Drug Targets Gene Transfer to the Central Nervous System: Current State of the Art of the Viral Vectors
Current Genomics Analysis of Homocysteine in Plasma of Rats Exposed to High-fat Diet and Chronic Unpredictable Mild Stress by LC/ESI-MS/MS
Current Analytical Chemistry Proteomic Analysis of Cerebrospinal Fluid: A Search for Biomarkers of Neuropsychiatric Systemic Lupus Erythematosus
Current Proteomics Defects in RNA Metabolism links FTD and ALS Pathogenesis: TDP-43, FUS, and C9orf72
Current Enzyme Inhibition Microtubules (tau) as an Emerging Therapeutic Target: NAP (Davunetide)
Current Pharmaceutical Design Blockade of Renin Angiotensin System in Heart Failure Post-Myocardial Infarction: What is the Best Therapy?
Recent Patents on Cardiovascular Drug Discovery In Silico Studies in Drug Research Against Neurodegenerative Diseases
Current Neuropharmacology N-Substituted Aryl Sulphonamides as Potential Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation
Current Computer-Aided Drug Design Current & Future Therapies of Erectile Dysfunction in Neurological Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Role of Dietary Polyphenols in Attenuating Brain Edema and Cell Swelling in Cerebral Ischemia
Recent Patents on CNS Drug Discovery (Discontinued) Heterocyclic Compounds as Anti-Inflammatory Agents
Current Bioactive Compounds Coenzyme Q10 for Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis
CNS & Neurological Disorders - Drug Targets Anderson-Fabry Disease in Children
Current Pharmaceutical Design