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Computer-Aided Drug Design Applied to Beta and Gamma Secretase Inhibitors-Perspectives for New Alzheimer Disease Therapy

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Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid plaques, containing the extracellular amorphous deposits of beta-amyloid protein and intracellular neurofibrillary tangles, comprising filaments of phosphorylated form of a microtubule-associated protein Tau, localized in the brain. It is considered that the major constituent of amyloid plaques, beta-amyloid peptide (Aβ), induces AD neuropathology. AD enzymatic pathway comprises several events: (i) beta-secretase cleaves amyloid precursor protein (APP) and releases a soluble fragment, beta-APPs, and (ii) gamma-secretase cleaves the C-terminal membrane bound C99 peptide within the transmembrane domain, thus generating two major amino acid isoforms of beta-amyloid: Aβ40 and Aβ42. This review is focused on the recent advances in the field of computational chemistry (molecular docking, 3D-QSAR (CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis)), molecular dynamics and rational drug design) applied to inhibitions of beta and gamma secretases. Computational chemistry studies have been performed for different inhibitors of beta and gamma secretases (e.g. benzodiazepine, urethane and tetrapeptide derivatives) resulting in their predicted biological activities and free energies.

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Keywords: Alzheimer's disease; computational chemistry; gamma and beta secretases inhibition

Document Type: Research Article

Affiliations: Department of Physiology & Biophysics, University of Bucharest, Faculty of Biology, 91-95, Splaiul Independentei R-76201, Bucharest, Romania.

Publication date: November 1, 2006

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  • Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.
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