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Selective anti-alzheimer multitargeting of bace-1 and acetylcholinesterase

Samba is an integrated drug discovery project that combines state-of-the-art molecular biology, informatics and medicinal chemistry methods to develop optimized pre-clinical candidates against alzheimer disease acting as inhibitors of bace-1 and acetylcholinesterase.

SAMBA is an integrated drug discovery project that combines state-of-the-art molecular biology, informatics and medicinal chemistry methods to develop optimized pre-clinical candidates against Alzheimer disease acting as inhibitors of BACE-1 and Acetylcholinesterase. The project idea is to design and develop drug candidates (leads) that simultaneously hit multiple Alzheimer’s disease biological targets with a favorable pharmacokinetic and selectivity profile. The candidates to be developed and designed are small molecules and peptides, subsequently to form the basis for peptidomimetics and peptide analogs. Several scientific evidence has demonstrated that AD is a complex neurodegenerative disorder resulting from multiple molecular abnormalities, and not from a single target/ gene defect. Multi-target-directed anti-AD-drugs could provide a more efficient therapy for AD treatment. Our approach is aimed at developing agents that should act on two or more targets implicated in AD, therefore we gather and use all structural, biological and pharmacological information as input data for model building. Significant research has been done on dual activity inhibitors hitting BACE-1 as well as AChE, However, the multitarget profile and efficiency should be improved not to effect other aspartic proteases as well as cholinesterases that could be responsible for side-effects and should be acting mainly in the central nervous system (CNS) thus having the need to cross the Blood-Brain Barrier(BBB). Both the in silico models developed (one for each of these two targets)will be applied to select potential active compounds with improved multitarget anti-AD activities from compound databases as well as to predict de novo compounds either with peptide, peptidomimetic or small molecule structures. These two lines (peptide/peptidomimeticand small molecules) of design and acquisition will be carried out in parallel leading to a primary screening collection of compounds (100-500) of both the peptides and the small molecules. These compound sets will be screened in cell-based assays on AD associated cell lines (e.g. PC12 cells are used as a model system for neuronal differentiation). The active compounds (that inhibit neuronal aggregation) would be further investigated in target-based assays in order to confirm and analyze the multi-target profile (BACE-1, AChE and selected isoforms). The compounds with acceptable multitarget profile will be used as input data for model refinement which ultimately leads to a multi-target focused library. This focused library will be evaluated by an extended cell-based assay portfolio including neuronal aggregation, and cytotoxicity related assays. The compounds that pass this stage will be again screened for multi-target profiling which will focus on achieving a balanced anti-amyloid/anticholinesterase affinity profile, as well as favorable off-target and anti-target properties. Compounds that meet the strict requirements for in vivo studies will be applied in animal investigations. The best compounds can be considered as the primary output of the project. Beside the lead candidate generation the project has additional objectives which support the consortium to achieve its main purpose. Short summary of the project objectives: 1. In silico model building for multitargets in AD 2. Identification of multitarget anti-AD focused libraries enriched in potential lead candidates 3. Development of cell-based and target-based anti-AD MTS assays testing potential anti-AD libraries. 4. Development of animal models for preclinical testing of the anti-AD drug candidates 5. Development of new R&D alliances inside the consortium, which are capable for the execution of multiple approach drug discovery projects through integration of various expertise 6. Development of a research infrastructure 7. Market oriented innovative products and services 8. Beside the main purpose of the project, the other objectives would mean significant progress in terms of research cooperation, infrastructure and development of market oriented innovative products and services.
Acronym: 
SAMBA
Project ID: 
7 211
Start date: 
15-11-2013
Project Duration: 
19months
Project costs: 
440 000.00€
Technological Area: 
Clinical Research, Trials
Market Area: 
Drug delivery and other equipment (including kidney dialysis machines)

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