Thesis  defense by  Laura TROUSSICOT “New approach based on molecular dynamics and NMR to study and optimize new inhibitors of human peroxiredoxins involved in ischemic strokes“, May 5, 2017 at 2 pm at the ISA meeting room

abstract :

Description of protein-ligand interactions is crucial for the understanding of all biological phenomena, and the drug design process. Thanks to new developments in computational devices, simulation of interaction equilibria using molecular dynamics are becoming state-of-the-art approach f or the microscopic study of these molecular interactions. These new methods guide the conception and the optimization of new biological inhibitors.

This project is focused on the use of funnel metadynamics for the prediction of protein- ligand affinities, and the description of interactions. Data obtained by metadynamics are correlated with experimental data from NMR and enzymatic assays. On the biological model of human peroxiredoxins, involved in the post ischemic inflammation cascade, interaction an inhibition of catechols derivatives have been studied. Data obtained from simulations have been used in the optimization process of the catechol fragment, to reach a better affinity and inhibition of human peroxiredoxins.

Our results have shown that funnel-metadynamics allows the prediction of protein-ligand affinities, and the realistic description of the interaction, that lead to identify and optimize new bioactive molecules. Their inhibitory strengths and mechanisms have been examinated using enzymatic assays.

Our research gives an overview of the possibilities brought by new numerical approaches, and their application in medicinal chemistry for example.