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Kinetics of protein-ligand unbinding via smoothed potential molecular dynamics simulations

Mercredi 27 mai 2015 14:00 - Duree : 1 heure
Lieu : MD-1-21, ESRF, 71 avenue des Martyrs, 38000 Grenoble

Orateur : Luca MOLLICA (CompuNet - IIT, Genoa)

Drug discovery is an expensive and high-risk process whose main reasons of failure are the lack of efficacy and the toxicity of a drug candidate. Binding affinity to the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy : it is indeed becoming increasingly evident that the time a drug spends in contact with its target (i.e., the residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays.

A recently developed molecular dynamics-based method will be presented as a simple and efficient computational approach to prioritize compounds according to their residence time in their binding site. A multiple-replica scaled molecular dynamics (SMD) protocol has been devised with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold, ranking ligands according to the mean observed scaled unbinding time. The approach, parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance and supported by statistical analysis.

Some other examples of ongoing computational studies with the aim of interpreting or predicting kinetic data in the area of drug discovery will be briefly discussed.

Contact : ferrero@esrf.fr

Discipline évènement : (Physique)
Entité organisatrice : (ESRF)
Nature évènement : (Séminaire)
Evènement répétitif : (SciSoft coffee meeting)
Site de l'évènement : Polygone scientifique

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