Kinetics of Drug Binding and Residence Time

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 applications reviewed here. However, we also consider kinetic Monte Carlo. We conclude with the outlook that drug (un)binding kinetics may soon become a go/no go step in the discovery and development of new medicines.

Equatorial Non-muscle Myosin II and Plastin Cooperate to Align and Compact F-actin Bundles in the Cytokinetic Ring

“…Assuming a diffusion-dominated recovery profile, the myosin dissociation rate (k off ) in Figure 3A' was calculated from FRAP data using the following equation (Bernetti et al, 2019):…”

Ligand binding free energy and kinetics calculation in 2020

“…The pharmacological activity of a drug persists as long as it remains bound to its molecular target. Under this concept, a number of methods have been proposed for the characterization of the LPB kinetics . These techniques have received a lot of attention in the last two decades since in vivo pharmacological activity of a drug was seen much dictated by the lifetime, also named residence time, of the binary drug‐protein complex, and not only by the thermodynamic stability of the ligand binding mode (binding affinity) .…”

“…In this review, we consider only the LPB of noncovalent ligands in which no formation of bond occurs upon ligand binding. As in most of the chemical processes, the theory behind the LPB is known and has been largely and rigorously reviewed in literature . Here, we report an overview of the basic theoretical concepts of LPB thermodynamics and kinetics that are relevant for the understanding of the computational methods discussed in the following sections.…”

Allosteric activation of metabotropic glutamate receptor 5

“…Computational studies are increasingly applied to explore the structural and dynamical properties of biological macromolecules including GPCRs (Bartuzi, Kaczor, & Matosiuk, 2018;Latorraca, Venkatakrishnan, & Dror, 2017) and among them mGluR receptors (Llinas del Torrent, P erez-Benito, & Tresadern, 2019). Molecular dynamics (MD) simulations are particularly valuable in investigating ligand binding (Bernetti, Masetti, Rocchia, & Cavalli, 2019;De Vivo, Masetti, Bottegoni, & Cavalli, 2016;Guo & IJzerman, 2018) and activation mechanism of GPCRs (Miao & McCammon, 2018;Yuan, Chan, et al, 2016;Yuan, Peng, Palczewski, Vogel, & Filipek, 2016). Here we used all-atom MD simulations to examine the effect of closely related allosteric ligands on the structure and activation of the mGluR5 receptor.…”