Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations

Journal of Chemical Theory and Computation
Daria B KokhRebecca C Wade

Abstract

Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compounds and less than 2.0τ within congeneric series. Analysis of dissociation trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.

References

Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Feb 7, 2006·Journal of Molecular Graphics & Modelling·Junmei WangDavid A Case
Sep 28, 2007·Journal of Computer-aided Molecular Design·John C ShelleyMakoto Uchimaya
Oct 7, 2008·European Biophysics Journal : EBJ·Mikael Peräkylä
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Mar 11, 2011·PLoS Computational Biology·Danzhi Huang, Amedeo Caflisch
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
May 21, 2011·Journal of Computational Chemistry·Mahmoud A A Ibrahim
Jun 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ignasi BuchGianni De Fabritiis
Jan 22, 2015·Proceedings of the National Academy of Sciences of the United States of America·Pratyush TiwaryMichele Parrinello
Jun 24, 2015·Scientific Reports·Luca MollicaWalter Rocchia
Sep 4, 2015·Journal of Chemical Information and Modeling·Andrea BortolatoJonathan S Mason
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Apr 8, 2014·Journal of Chemical Theory and Computation·Matteo SalvalaglioMichele Parrinello
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
Jan 26, 2016·Journal of Medicinal Chemistry·Marco De VivoAndrea Cavalli
Apr 30, 2016·British Journal of Pharmacology·Georges Vauquelin
May 10, 2016·Journal of Chemical Theory and Computation·Ivan TeoTony Lelièvre
May 28, 2016·The Journal of Physical Chemistry. B·Alex Dickson, Samuel D Lotz
Jan 13, 2017·Journal of Chemical Information and Modeling·Donatella CallegariAnna Maria Capelli
Mar 4, 2017·Biophysical Journal·Alex Dickson, Samuel D Lotz
Mar 16, 2017·Journal of the American Chemical Society·Rodrigo CasasnovasMichele Parrinello
Jun 6, 2017·Science Advances·Pratyush TiwaryB J Berne
Nov 14, 2017·Current Opinion in Structural Biology·Neil J BruceRebecca C Wade
Jan 6, 2018·Journal of the American Chemical Society·Samuel D Lotz, Alex Dickson
Apr 28, 2018·Journal of Medicinal Chemistry·Doris Alexandra SchuetzGerhard F Ecker

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Citations

Dec 26, 2018·Current Topics in Medicinal Chemistry·Dinler A AntunesLydia E Kavraki
Nov 6, 2018·Scientific Reports·Stefano MottaLaura Bonati
Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Aug 25, 2018·Journal of Computer-aided Molecular Design·Tom DixonAlex Dickson
Jan 24, 2019·Frontiers in Chemistry·Sérgio M MarquesJiri Damborsky
Feb 21, 2019·Annual Review of Physical Chemistry·Mattia BernettiAndrea Cavalli
Jun 11, 2019·Frontiers in Molecular Biosciences·Daria B KokhRebecca C Wade
Jun 17, 2019·The Journal of Chemical Physics·Jakub Rydzewski, Omar Valsson
Jun 12, 2020·Nature Communications·Steffen WolfGerhard Stock
Jun 26, 2020·Frontiers in Molecular Biosciences·Robert HallAlex Dickson
Nov 19, 2019·Frontiers in Chemistry·Gaspar P PintoJiri Damborsky
Apr 8, 2020·International Journal of Molecular Sciences·Shuheng HuangXianchao Pan
Jan 6, 2019·Applied Microbiology and Biotechnology·Vera VilValery M Dembitsky
Oct 10, 2020·The Journal of Chemical Physics·Nicole M Roussey, Alex Dickson
Jan 27, 2021·Cell Chemical Biology·Benedict-Tilman BergerStefan Knapp
Dec 18, 2020·Frontiers in Molecular Biosciences·Alex Bunker, Tomasz Róg
Jan 30, 2021·Biotechnology Advances·Joan Planas-IglesiasDavid Bednar
Dec 6, 2020·Marine Drugs·Ekaterina V ErmolenkoValery M Dembitsky
Oct 3, 2020·Chemical Reviews·Sergio Decherchi, Andrea Cavalli
Feb 21, 2021·Scientific Reports·Tyler GrearDonald J Jacobs
Feb 11, 2020·Biochemical and Biophysical Research Communications·Valery M DembitskyVladimir D'yakonov
Mar 1, 2020·Current Opinion in Structural Biology·Benjamin R JaggerAdrian J Mulholland
May 6, 2021·Journal of Biomolecular Structure & Dynamics·Andrés Felipe Vásquez, Andrés Fernando González Barrios
Jun 3, 2021·International Journal of Molecular Sciences·Bin Sun, Peter M Kekenes-Huskey
Jul 3, 2021·Marine Drugs·Valery M DembitskyVladimir V Poroikov
Jul 9, 2021·Current Research in Structural Biology·Ariane Nunes-AlvesRebecca C Wade
Jul 22, 2021·Journal of Biomolecular Structure & Dynamics·Saba RezvaniNima Razzaghi-Asl
Jul 2, 2021·Journal of Chemical Information and Modeling·Ariane Nunes-AlvesRebecca C Wade
Mar 21, 2019·Journal of Chemical Theory and Computation·Andrew PottertonAndrea Townsend-Nicholson
May 10, 2020·Journal of Chemical Information and Modeling·Kara J CutronaWilliam L Jorgensen
Aug 6, 2019·Journal of Chemical Information and Modeling·Neil J BruceRebecca C Wade
Nov 14, 2020·Journal of Chemical Information and Modeling·Nurlybek AmangeldiulyMaxim V Fedorov
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Aug 23, 2019·Journal of Chemical Theory and Computation·Mattia BernettiAndrea Cavalli
Jun 25, 2020·Journal of Chemical Theory and Computation·Benjamin R JaggerRommie E Amaro
Sep 12, 2019·Journal of Chemical Theory and Computation·Indrajit Deb, Aaron T Frank
Dec 1, 2018·Journal of Chemical Information and Modeling·Doris A SchuetzAndrea Cavalli
Aug 23, 2019·The Journal of Physical Chemistry. B·Ettayapuram Ramaprasad Azhagiya SingamKathleen A Durkin
Oct 20, 2018·Journal of Chemical Information and Modeling·Mattia BernettiAndrea Cavalli
Jun 28, 2019·Journal of Chemical Theory and Computation·Dorothea GobboAndrea Cavalli
Mar 4, 2020·Journal of Chemical Information and Modeling·Giuseppe DeganuttiChristopher A Reynolds

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