In Vitro and In Silico Analysis of the Residence Time of Serotonin 5-HT7 Receptor Ligands with Arylpiperazine Structure: A Structure- Kinetics Relationship Study

During the last decade, the kinetics of drug-target interaction has received increasing attention as an important pharmacological parameter in the drug development process. Several studies have suggested that the lipophilicity of a molecule can play an important role. To date, this aspect has been studied for several G protein-coupled receptors (GPCRs) ligands but not for the 5-HT7 receptor (5-HT7R), a GPCR proposed as a valid therapeutic target in neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. In this study, we report on structure-kinetics relationships of a set of arylpiperazine-based 5-HT7R ligands. We found that it is not the overall lipophilicity of the molecule that influences drug-target interaction kinetics but rather the position of polar groups within the molecule. Next, we performed a combination of molecular docking studies and molecular dynamics simulations to gain insights into structure-kinetics relationships. These studies did not suggest specific contact patterns between the ligands and the receptor-binding site as determinants for compounds kinetics. Finally, we compared the abilities of two 5-HT7R agonists with similar receptor-binding affinities and different residence times to stimulate the 5-HT7R-mediated neurite outgrowth in mouse neuronal primary cultures and found that the compounds induced the effect with different timing. This study provides the first insights into the binding kinetics of arylpiperazine-based 5-HT7R ligands that can be helpful to design new 5-HT7R ligands with fine-tuning of the kinetic profile.

Automated summary

The kinetics of drug-target interaction has been a topic of increasing interest in the field of pharmacology. Previous studies have shown the importance of the lipophilicity of a molecule in this process, but there has been limited research on the 5-HT7 receptor (5-HT7R), a GPCR involved in neurodevelopmental and neuropsychiatric disorders. In this study, the researchers explored the structure-kinetics relationships of a specific class of ligands for the 5-HT7R and found that the position of polar groups within the molecule, rather than overall lipophilicity, influenced the interaction kinetics. Additionally, molecular docking and dynamics simulations were used to gain further insights into the relationship between structure and kinetics.