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BP83 - 59006 - Lille Cedex
59000 - Lille
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NOD1 antagonists

A new project on the design and synthesis of NOD1 antagonists is the result of a collaboration with team 1 of the LIRIC (Inserm U995) directed by Dr. Laurent Dubuquoy. Up to now, only few NOD1 modulators have been described and the discovery of NOD1 signaling pathway inhibitors is very recent. In the literature, studies are based on high throughput screening and not on a biological rational or molecular interaction hypothesis.

NOD1 recognizes a tetrapeptidic pattern (GM-triDAP) mainly present in the peptidoglycan of Gram negative bacteria and seems to regulate immune defense mechanism involving polymorphonuclear neutrophil (PMN). In a recent study, Laurent Dubuquoy et al. have demonstrated that NOD1 is an intrinsic regulator essential for the migration and phagocytosis functions of PMN.

The structure of the ligand recognition site is only partially described due to directed mutagenesis studies. Based on these works, we have built a tridimensional model of NOD1 showing the ligand-NOD1 interactions at an atomic level and antagonists described in the literature have been docked in this model.

Following the original approach of molecular modeling, we have designed in silico molecules, which could interact with the amino acids involved in NOD1 antagonist activity. Through this de novo design strategy, several series of potential antagonists have been proposed and will be synthesized.