Kinetic evaluation from the perspective of drug discovery

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Drug discovery is expensive and time-consuming

One of the important factors determining the success of drug discovery is in vivo pharmacokinetics

01 The importance of dynamics

Drug discovery typically involves the identification and optimization of lead compounds through a series of in vitro experiments at constant drug concentrations

However, when drugs enter the human body, their concentrations are constantly changing due to physiological processes such as gastrointestinal absorption, renal excretion, and metabolism

02 Association and dissociation rates

The two most basic units to characterize dynamic drug interactions are the association rate constant (association rate constant/on-rate, kon) and the dissociation rate constant (dissociation rate constant/off-rate, koff)

While there have been many studies on koff and how to reduce it, there are relatively few data on koff and its effect on target occupancy in vivo

IJzerman and Guo argue that one reason why research on kon has been given less attention is that there are questions about common assumptions about the measure

03 Experimental tools

It is known that there are various techniques to measure kon and koff, one of the oldest is radioligand binding assay, but it has some limitations, such as difficulty in separating radiolabeled ligand from free ligand

A popular, label-free method is surface plasmon resonance (SPR), in which the formation of drug-target complexes causes a change in the refractive index of polarized light

Arguably, the most widely used techniques are fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) due to their high sensitivity, compatibility with living cell states, and the ability to commercially design fluorescent probes for a variety of proteins

The mechanisms of these two methods are similar and rely on the distance-dependent transfer of energy from the donor molecule to the acceptor molecule

Other emerging methods include quartz crystal microbalances, which detect mass changes due to ligand binding to cells, and fluorescence correlation spectroscopy, which measures fluctuations in particle fluorescence intensity, where free ligands can interact with slowly diffusing receptors.

The growing emphasis on pharmacokinetics led to the K4DD (Kinetics for Drug Discovery, Kinetics of Drug Discovery) project, funded by the European Innovative Medicines Initiative (IMI) and large pharmaceutical companies

04 Computational Modeling Tools

The molecular understanding of the dynamics of drug-target interactions has improved with advances in X-ray crystallography and electron microscopy

For example, dissociation of benzene creates a cavity in lysozyme, which affects protein properties such as denaturation temperature and binding to specific ligands

05 Looking to the future

The human body is constantly changing, so capturing dynamic pharmacokinetics is a challenge

Further confirming its importance, kinetic selectivity in turn affects target vulnerability, defined as the proportion of targets that must engage in binding to elicit a desired response
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Low-vulnerability targets require relatively higher levels of drug exposure compared to high-vulnerability targets to achieve pharmacologically relevant levels of target engagement
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This means that highly vulnerable targets are strongly influenced by kinetic selectivity, as more time is required to generate a small fraction of active targets (eg, target engagement through drug dissociation after binding)
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Although predicting pharmacokinetics is complex, as experimental and modeling approaches continue to improve, better predictions are expected to improve drug efficacy and safety
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Reference: Andy Tay, PhD: Assessing Kinetics in Drug Discovery