• Aucun résultat trouvé

Computational Tools for Protein-Ligand Binding Kinetics in Personalized Medicine

N/A
N/A
Protected

Academic year: 2022

Partager "Computational Tools for Protein-Ligand Binding Kinetics in Personalized Medicine"

Copied!
1
0
0

Texte intégral

(1)

Wouter Vervust

COMPUTATIONAL TOOLS FOR PROTEIN-LIGAND BINDING KINETICS IN PERSONALIZED MEDICINE Wouter Vervust (1), An Ghysels (1)

(1) Biofluid, Tissue and Solid Mechanics for Medical Applications (bioMMeda), Ghent University, Ghent, Belgium

Patients with the fusion oncoprotein BCR-ABL develop chronic myeloid leukaemia, where the ki nase domain of ABL is constitutively active instead of auto-inhibited. Tyrosine kinase inhibitors (TKIs) have been developed that competitively bind to the ATP binding site of ABL, minimizing ABL’s e nzymatic function of transferring phosphate groups to substrate proteins. Mutations in the kinase domai n of ABL can reduce – or completely block – the binding activity of known TKIs, to which the need of novel and personalized drug molecules arises. s

In this study, state-of-the-art molecular dynamics simulation techniques are being used to extract both thermodynamical and kinetical information of ABL-inhibitor complexes, for multiple inhibitors, and for multiple ABL mutations. Kinetic descriptors of protein-drug complexes, such as drug residence time, have recently been shown to be important for predicting the in vivo efficacy of candidate drug molecules. Computational tools to predict binding kinetics are there fore ne e ded i n the screening stages of the drug-design pipeline; however, the time-depende nt nature of ki ne ti cs makes it a challenging subject for current computational resources.

Replica Exchange Transition Interface Sampling (RETIS) is used to calculate drug (un)binding rates and residence times, where it is currently set up for imatinib and wildtype ABL as a proof of concept.

Unlike biasing techniques, RETIS delivers trajectories with the intrinsic dynamics untouched, allowing also qualitative comparisons between different inhibitors/mutations. In the future , we wi ll e xtend the RETIS method to the general case of protein-ligand binding, where it can be a useful tool in precision medicine and drug design.

Références

Documents relatifs

Comparison of the space required for RTV binding to the size of the pocket in the unliganded protease also suggests a structural mechanism contributing to RTV resistance: In

The addition of increasing amounts of PK 11195 induced increasing changes in the CD spectrum, as shown in Figure 1, but required high ligand over protein molar ratios (inset of

We hope that ongoing studies will document interaction of TB5 domain and ADAMTSL2 and contribute to a greater understanding of how enhanced TGFb signaling caused by FBN1 mutations

Extending pathways and processes using molecular interaction networks to analyse cancer genome data, BMC Bioinformatics, 11(1):597, 2010. Toward omics-based, systems biomedicine,

Glaciers in the studied valleys of the central Jablanica Mt. during the Vev čani Phase. The reconstructed glacier systems occupied an area of 20.7 km 2 , the longest glacier in

en Août et un second en Décembre. L'élevage des mâles d'abord et des reines ensuite et la naissance des essaims ont lieu au cours de ces périodes de grande

Under the assumption that the joint distribution has a density that is continuous in A ; B and C, we provide necessary and sufficient conditions under which the intersection

Replica Exchange Transition Interface Sampling (RETIS) [1] is an exact path sampling method.. RETIS uses an initial trajectory to generate new trajectories using shooting moves,