Ligand-receptor binding kinetics in drug design

Abstract

Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured in vitro at steady concentrations of the receptor and ligand, which are differed from in vivo environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness. This has increased attention in characterizing and predicting the rate constants of association and dissociation of the receptor ligand at the stage of preclinical studies of drug candidates. A drug with a long residence time can determine ligand-receptor selectivity (kinetic selectivity), maintain pharmacological activity of the drug at its low concentration in vivo. The paper discusses the theoretical basis of protein-ligand binding, molecular determinants that control the kinetics of the drug-receptor binding. Understanding the molecular features underlying the kinetics of receptor-ligand binding will contribute to the rational design of drugs with desired properties.

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

“…However, the difference in free energy between the correct and wrong target may be insignificant or absent [ 58 ], which significantly limits the use of affinity for determining the specificity of the TCR-pMHC interaction [ 59 , 60 ]. A similar paradox is well known in biochemistry for many molecular interactions; for example, during protein synthesis, each mRNA codon selectively interacts with a specific tRNA anticodon [ 59 , 61 ].…”

“…In biological systems, the kinetics of ligand–receptor interactions is no less significant than affinity for the reason that different processes require time [ 58 ]. Equation (2) shows that the affinity expressed in terms of the association constant is equal to the ratio of the two rate constants.…”

“…Equation (2) shows that the affinity expressed in terms of the association constant is equal to the ratio of the two rate constants. Therefore, with the same affinity, the reaction kinetics can be different if the association and dissociation rates are proportionally different [ 56 , 58 ]. The rates are determined by the difference in free energy between stable and transient states, whereas affinity is the difference in free energy between unbound and bound state ( Figure 1 ).…”

“…The rates are determined by the difference in free energy between stable and transient states, whereas affinity is the difference in free energy between unbound and bound state ( Figure 1 ). As noted above, various processes, whether enzymatic reactions or TCR activation, require time, i.e., the interaction efficiency depends on the stability of the ligand–receptor complex [ 58 , 69 ]. Quantitatively, stability is expressed by the complex lifetime or residence time, which is inversely proportional to the dissociation constant: …”

“…The residence time depends on a combination of various factors that affect the relative free energies of the stable and transient states, and it follows from Equations (2) and (5) that low affinity is not always associated with short residence time [ 56 , 58 , 70 ]. Thus, along with affinity, the specificity of the interaction in many irreversible processes is provided by kinetic selectivity ( ): where pMHC 1 and pMHC 2 are the competing ligands [ 58 ].…”