Design strategies to address kinetics of drug binding and residence time

Bioorganic & Medicinal Chemistry Letters
Kevin P CusackAnil Vasudevan

Abstract

The kinetics of drug binding and drug residence time are recognized to be important in the clinical effectiveness of drug candidates. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concentrations of drug have been notably reduced through elimination routes. Hence, if selective for target, long residence times can increase the duration of drug efficacy in vivo and can significantly diminish the potential for off-target-mediated toxicities. Furthermore, a compound with a slower dissociation rate may allow a reduced dosing schedule relative to a compound with a rapid dissociation rate. Factors contributing to long residence time that could be useful to medicinal chemists in the prospective design of compounds with long residence times will be discussed in this perspective. Particular emphasis will be on case studies highlighting how kinetics can be measured, modulated based on supporting structure kinetic relationships and whether these effects are translatable into man.

References

May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·D L BogerB F Cravatt
Aug 25, 2006·Nature Reviews. Cancer·Kohzoh Imai, Akinori Takaoka
Apr 17, 2008·Biochemistry·Peter J Tummino, Robert A Copeland
Jan 6, 2009·Drug Discovery Today·Irini Akritopoulou-Zanze, Philip J Hajduk
Sep 3, 2011·Future Medicinal Chemistry·Robert A Copeland
Feb 4, 2012·Current Pharmaceutical Design·Dominique Charmot
Feb 15, 2012·Naunyn-Schmiedeberg's Archives of Pharmacology·Georges VauquelinPhilip Seeman
May 25, 2012·Journal of Medicinal Chemistry·Tjeerd Barf, Allard Kaptein
Aug 7, 2012·Expert Opinion on Drug Discovery·Ye Fang
Sep 18, 2012·Chemical Biology & Drug Design·Aravind BasavapathruniEdward J Olhava
Oct 25, 2012·Expert Opinion on Therapeutic Patents·Scott D Kuduk, Douglas C Beshore
Dec 13, 2012·Expert Opinion on Drug Discovery·Xuqing Zhang, Zhihua Sui
Dec 7, 2013·ACS Chemical Biology·Glenn S Van AllerRyan G Kruger
Jan 10, 2014·Chembiochem : a European Journal of Chemical Biology·Darja LavoginaAsko Uri

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Citations

Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
Jan 3, 2016·Drug Discovery Today. Technologies·Mary Ellen CvijicLitao Zhang
Nov 26, 2015·Future Medicinal Chemistry·Tjerk BuetersSandra A G Visser
Jan 26, 2016·British Journal of Pharmacology·Georges VauquelinDavid C Swinney
Oct 29, 2015·Journal of Medicinal Chemistry·Peng ZhanXinyong Liu
Apr 18, 2015·Biochimica Et Biophysica Acta·Roland G HeymGeorg C Terstappen
Apr 30, 2016·British Journal of Pharmacology·Georges Vauquelin
Aug 16, 2016·Nature Reviews. Drug Discovery·Jean-Paul RenaudHerbert Nar
Apr 19, 2017·Journal of Chemical Theory and Computation·Zhiye Tang, Chia-En A Chang
Oct 18, 2016·MedChemComm·Jed F Fisher, Shahriar Mobashery
Aug 25, 2017·British Journal of Pharmacology·Georges Vauquelin
Nov 10, 2018·The Journal of Biological Chemistry·Tai WangGabriela Chiosis
Mar 12, 2019·Integrative Biology : Quantitative Biosciences From Nano to Macro·Duo ZhangLinxin Chen
Mar 6, 2019·Current Pharmaceutical Design·Nizar A Al-Shar'i, Qosay A Al-Balas
Feb 25, 2017·Journal of Molecular Recognition : JMR·Megan L PeachMarc C Nicklaus
Feb 21, 2019·Annual Review of Physical Chemistry·Mattia BernettiAndrea Cavalli
Nov 7, 2020·Trends in Pharmacological Sciences·Georges VauquelinDavid C Swinney
Jan 7, 2018·Biochemical Pharmacology·Lizi XiaLaura H Heitman
Sep 7, 2017·Journal of Medicinal Chemistry·Christopher L Cioffi
Nov 10, 2017·Journal of Medicinal Chemistry·Ganesha RaiDavid J Maloney
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Oct 20, 2018·Journal of Chemical Information and Modeling·Mattia BernettiAndrea Cavalli
Nov 4, 2021·Expert Opinion on Drug Discovery·Qianqian ZhangHuanxiang Liu

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