Fluorinated Protein–Ligand Complexes: A Computational Perspective

Wehrhan, Leon; Keller, Bettina G.

doi:10.1021/acs.jpcb.4c01493

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2024

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References 86 publications

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“…In particular, inaccuracies have been observed when the halogen interacts with Lewis bases. However, fluorine's small sigma hole can be adequately described with a point charge 29 , as shown by the successful application of SEEKR to the TTK 5NAD and 2X9E systems, which contain many fluorines.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics

Votapka,

Ojha,

Asada

et al. 2024

Preprint

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Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times. Using the pharmaceutically relevant threonine-tyrosine kinase (TTK) and eight long-residence-time (tens of seconds to hours) inhibitors, we demonstrate accurate prediction of absolute and rank-ordered ligand residence times and free energies of binding.TOC Graphic

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Section: Introductionmentioning

confidence: 99%