Kinetics of Drug Binding and Residence Time

Annual Review of Physical Chemistry
Mattia BernettiAndrea Cavalli

Abstract

The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/koff). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy). There are many experimental and computational methods for predicting drug-target residence time at an early stage of drug discovery programs. Here, we review and discuss the methodological approaches to estimating drug binding kinetics and residence time. We first introduce the theoretical background of drug binding kinetics from a physicochemical standpoint. We then analyze the recent literature in the field, starting from the experimental methodologies and applications thereof and moving to theoretical and computational approaches to the kinetics of drug binding and unbinding. We acknowledge the central role of molecular dynamics and related methods, which comprise a great number of the computational methods and applica...Continue Reading

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Citations

Jul 2, 2019·Journal of Biomolecular Structure & Dynamics·Balázs JójártGyörgy M Keserű
Jul 17, 2020·Frontiers in Molecular Biosciences·Joseph M Rogers
Sep 24, 2020·Pharmaceuticals·Mattia BernettiMatteo Masetti
Feb 2, 2021·Journal of Chemical Information and Modeling·André FischerMartin Smieško
Oct 3, 2020·Chemical Reviews·Sergio Decherchi, Andrea Cavalli
Mar 1, 2020·Current Opinion in Structural Biology·Benjamin R JaggerAdrian J Mulholland
Nov 22, 2020·Drug Discovery Today·Hershna Patel, Andreas Kukol
Mar 31, 2021·Physical Review Letters·Brandon R FerrerAlejandro V Arzola
May 28, 2021·Frontiers in Molecular Biosciences·Shivansh Kaushik, Chia-En A Chang
Sep 21, 2019·Journal of Chemical Information and Modeling·Jure BorišekAlessandra Magistrato
Jul 9, 2021·Current Research in Structural Biology·Ariane Nunes-AlvesRebecca C Wade
Aug 6, 2019·Journal of Chemical Information and Modeling·Neil J BruceRebecca C Wade
Aug 23, 2019·Journal of Chemical Theory and Computation·Mattia BernettiAndrea Cavalli
Oct 9, 2019·Analytical Chemistry·Guangzhong MaNongjian Tao
Apr 22, 2020·Journal of Chemical Information and Modeling·Surl-Hee AhnRommie E Amaro
Jul 17, 2020·Journal of Medicinal Chemistry·Muhammad Murtaza HassanPatrick T Gunning
Aug 22, 2020·Journal of the American Chemical Society·Cristina García-SimónXavi Ribas
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Nov 4, 2021·Expert Opinion on Drug Discovery·Qianqian ZhangHuanxiang Liu
Jul 3, 2021·Expert Opinion on Drug Discovery·Robert A Copeland

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Methods Mentioned

BETA
surface plasmon resonance
BRET
isothermal titration calorimetry

Software Mentioned

MuITC
BiKi
kMC
SEEKR
Simulation Enabled Estimation of Kinetic Rates ( SEEKR )
RAMD
kinITC
WExplore
MetaD
sMD

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