Uncovering the unique characteristics of different groups of 5-HT5AR ligands with reference to their interaction with the target protein

Abstract

Background: The serotonin 5-HT_5A receptor has attracted much more research attention, due to the therapeutic potential of its ligands being increasingly recognized, and the possibilities that lie ahead of these findings. There is a growing body of evidence indicating that these ligands have procognitive, pro-social, and anti-depressant properties, which offers new avenues for the development of treatments that could address socially important conditions related to the malfunctioning of the central nervous system. The aim of our study was to unravel the molecular determinants for 5-HT_5AR ligands that govern their activity towards the receptor.

Methods: In response to the need for identification of molecular determinants for 5-HT_5AR activity, we prepared a comprehensive collection of 5-HT_5AR ligands, carefully gathering literature and patent data. Leveraging molecular modeling techniques, such as pharmacophore hypothesis development, docking, and molecular dynamics simulations enables to gain valuable insights into the specific interactions of 5-HT_5AR ligand groups with the receptor.

Results: The obtained comprehensive set of 2160 compounds was divided into dozens of subsets, and a pharmacophore model was developed for each group. The results from the docking and molecular dynamics simulations have enabled the identification of crucial ligand-protein interactions that are essential for the compound's activity towards 5-HT_5AR.

Conclusions: The findings from the molecular modeling study provide valuable insights that can guide medicinal chemists in the development of new 5-HT_5AR ligands. Considering the pharmacological significance of these compounds, they have the potential to become impactful treatments for individuals and communities in the future. Understanding how different crystal/cryo-EM structures of 5-HT_5AR affect molecular modeling experiments could have major implications for future computational studies on this receptor.

Keywords: 5-HT5AR; Docking; Ligand database; Molecular dynamics; Pharmacophore modeling; Serotonin receptors.

Fig. 1

Scheme of the study

Fig. 2

Distribution of activity parameters values of 5-HT_5AR ligands deposited in the ChEMBL database (orange lines refer to step changes in the scale), a K_i, b IC₅₀, c EC₅₀, d Venn diagram for particular parameters values determined for 5-HT_5AR ligands, created on-line at https://bioinformatics.psb.ugent.be/webtools/Venn/; e the number of records present in the ChEMBL database referring to different serotonin receptor subtypes

Fig. 3

The most populated clusters of known 5-HT_5AR ligands together with the distribution of the K_i values within each cluster and pharmacophore model developed for each group of compounds

Fig. 4

Examples of less populated groups of 5-HT_5AR ligands

Fig. 5

Visualization of example 5-HT_5AR crystal structures: 4UM4 (gray), and 4UM5 (orange)

Fig. 6

The interaction frequency of the most populated clusters of 5-HT_5AR ligands with the 7UM4 crystal structure (positions making contact with more than 60% of compounds from at least one of the considered groups are presented)

Fig. 7

Docking poses of representatives of 2-aminoquinolines (orange) and acylguanidines (magenta) of structures presented in Fig. 3

Fig. 8

Amino acids with the highest difference in the ligand–protein interaction frequency between active (K_i < 1000 nM) and inactive (K_i > 1000 nM) compounds observed for different 5-HT_5AR crystal structures: a 7UM4, b 7UM5, c 7UM6, d 7UM7; amino acid numbering according to the GPCRdb scheme

Fig. 9

Amino acids with the highest difference in the ligand–protein interaction frequency between 5-HT_5AR antagonists (IC₅₀ < 1000 nM) and inactive compounds (IC₅₀ > 1000 nM)

Fig. 10

Amino acids with the highest difference in the ligand–protein interaction frequency between 5-HT_5AR agonist (EC₅₀ < 1000 nM) and inactive compounds (EC₅₀ > 1000 nM) for different crystal structures: a 7UM5, b 7UM6, c 7UM7

Fig. 11

a Structures and activities of compounds examined in the molecular dynamics simulation studies, b selected compound conformations obtained in the MD for different time steps of the simulation: firebrick—starting conformation, cyan: 250 ns, magenta: 500 ns, yellow: 750 ns, salmon: 1000 ns.

Fig. 12

Mutagenetic data available for the 5-HT_5AR; figure created with the use of the GPCRdb service [36]; yellow color indicates change of the ligand binding affinity upon particular residue mutation