Determinants of drug-target interactions at the single cell level

Abstract

The physiochemical determinants of drug-target interactions in the microenvironment of the cell are complex and generally not defined by simple diffusion and intrinsic chemical reactivity. Non-specific interactions of drugs and macromolecules in cells are rarely considered formally in assessing pharmacodynamics. Here, we demonstrate that non-specific interactions lead to very slow incorporation kinetics of DNA binding drugs. We observe a rate of drug incorporation in cell nuclei three orders of magnitude slower than in vitro due to anomalous drug diffusion within cells. This slow diffusion, however, has an advantageous consequence: it leads to virtually irreversible binding of the drug to specific DNA targets in cells. We show that non-specific interactions drive slow drug diffusion manifesting as slow reaction front propagation. We study the effect of non-specific interactions in different cellular compartments by permeabilization of plasma and nuclear membranes in order to pinpoint differential compartment effects on variability in intracellular drug kinetics. These results provide the basis for a comprehensive model of the determinants of intracellular diffusion of small-molecule drugs, their target-seeking trajectories, and the consequences of these processes on the apparent kinetics of drug-target interactions.

Overcoming Compensatory Mechanisms toward Chronic Drug Administration to Ensure Long-Term, Sustainable Beneficial Effects

“…The variable interactions in different cellular compartments contribute to the variability in intracellular drug kinetics. 59 Many of the functions of the microtubules manifest as distinct variability patterns. 39 , 60 Ongoing dynamic changes in the strength of synaptic connections in excitatory neurons occur when calcium ions Ca 2+ bind the Ca 2+ sensor, calmodulin (CaM), thus contributing to synaptic plasticity.…”

Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies

“…The inter- and intra-individual variability described in the response toward drugs has been attributed partly to pharmacogenomics- and pharmacodynamics-based drug metabolism, and drug responsiveness (119–122). However, there is heterogeneity between individual cells in their response to drugs (123). Complex physiochemical determinants of drug-target interactions in a cell have been described and are not defined by simple diffusion and intrinsic chemical reactions.…”

“…The non-specific interactions of drugs and macromolecules in cells are beyond “simple” pharmacodynamics, affect drug function, and are difficult to control for. Non-specific interactions greatly slow the incorporation kinetics of DNA-binding drugs and have been attributed to anomalous drug diffusion in cells (123). Differential cell compartment effects affect intracellular drug kinetics variability (123).…”

“…Non-specific interactions greatly slow the incorporation kinetics of DNA-binding drugs and have been attributed to anomalous drug diffusion in cells (123). Differential cell compartment effects affect intracellular drug kinetics variability (123). There is marked intra-patient variability in drug serum levels between days, suggesting additional underlying mechanisms (122, 124).…”

Targeting SARS-CoV-2 receptors as a means for reducing infectivity and improving antiviral and immune response: an algorithm-based method for overcoming resistance to antiviral agents

“…Individual tolerance to drugs is a random variable that derives from multiple genetic and environmental factors, which suggests that deterministic equations are not suitable for modelling it. Variability of the treatment response has been attributed to pharmacogenomic- and pharmacodynamic-based drug metabolism parameters, but the heterogeneity in the responses cannot be attributed solely to these factors [ 90 ]. Complex intracellular drug-target and drug-receptor interactions have been described.…”