scholarly journals The implications of target saturation for the use of drug–target residence time

2018 ◽  
Vol 18 (1) ◽  
pp. 84-84 ◽  
Author(s):  
Wilhelmus E. A. de Witte ◽  
Meindert Danhof ◽  
Piet H. van der Graaf ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Residence Time ◽  
Drug Target

Kinetics of Drug Binding and Residence Time

2019 ◽  
Vol 70 (1) ◽  
pp. 143-171 ◽  
Author(s):  
Mattia Bernetti ◽  
Matteo Masetti ◽  
Walter Rocchia ◽  
Andrea Cavalli
Keyword(s):  
Computational Methods ◽  
Residence Time ◽  
Drug Target ◽  
Early Stage ◽  
Kinetic Constant ◽  
Theoretical Background ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Kinetics Of

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.

scholarly journals Correlating drug–target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase

2016 ◽  
Vol 7 (9) ◽  
pp. 5945-5954 ◽  
Author(s):  
Fereidoon Daryaee ◽  
Andrew Chang ◽  
Johannes Schiebel ◽  
Yang Lu ◽  
Zhuo Zhang ◽  
...  
Keyword(s):  
Residence Time ◽  
Drug Target ◽  
Drug Activity ◽  
Enoyl Acp Reductase

A mechanistic PK/PD model that enables predictions ofin vivodrug activity and an assessment of target vulnerability.

Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Correlating Drug–Target Residence Time and Post-antibiotic Effect: Insight into Target Vulnerability

2020 ◽  
Vol 6 (4) ◽  
pp. 629-636
Author(s):  
Shabnam Davoodi ◽  
Fereidoon Daryaee ◽  
Andrew Chang ◽  
Stephen G. Walker ◽  
Peter J. Tonge
Keyword(s):  
Residence Time ◽  
Drug Target ◽  
Antibiotic Effect ◽  
Insight Into ◽  
Post Antibiotic Effect

Investigating Drug–Target Residence Time in Kinases through Enhanced Sampling Simulations

2019 ◽  
Vol 15 (8) ◽  
pp. 4646-4659 ◽  
Author(s):  
Dorothea Gobbo ◽  
Valentina Piretti ◽  
Rita Maria Concetta Di Martino ◽  
Shailesh Kumar Tripathi ◽  
Barbara Giabbai ◽  
...  
Keyword(s):  
Residence Time ◽  
Drug Target ◽  
Enhanced Sampling
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