Conception de ligands inhibiteurs de MT5-MMP (MMP-24) : implication dans le traitement de la maladie d'Alzheimer
Year: 2019
Type: dissertation
Abstract: Alzheimer’s Disease (AD) is lacking any curing therapy. Among the damages of AD we can find aggregated β-amyloid peptides in senile plaques. These peptides derive from the amyloid precursor protein (APP) cleavage by the β- et γ-secretases. Another APP metabolic pathway, the η-secretase pathway, is of interest for AD therapeutic novelties. This pathway leads to the secretion of neurotoxic peptides in the hippocampus, which is the site of long-term memory. η-secretase is a trans-membrane matrix metalloproteinase (MT-MMP). In the central nervous system, the η-secretase corresponds to MT5-MMP (or MMP-24). Genetic knockout of MT5-MMP shows a curative interest in AD in vivo models. However, MT5-MMP structural data are still lacking and this hinders the conception of potentially MT5-MMP inhibitory drugs. In 2016, the CERMN constructed an in silico model of the MT5-MMP catalytic domain, which allowed to discover a hit for the conception and synthesis of an inhibitory ligand of MT5-MMP. In this present work, the challenge was to assess several Ligand-Target binding mode hypotheses in order to propose pharmacomodulations. This is an in silico project. This manuscript is divided into three parts and proposes first a presentation of the Matrix Metalloproteinases and AD, second a presentation of the involvement of Chemoinformatics in Drug Design, and finally a presentation of the work of designing MT5-MMP inhibitory ligands for AD.
Source: HAL
Author: Johanna Giovannini
Institution: Université de Caen Normandie
Language: French
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3008444996