Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome

Abstract

Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS.

Predicting or Pretending: Artificial Intelligence for Protein-Ligand Interactions Lack of Sufficiently Large and Unbiased Datasets

“…Structure-based virtual screening (molecular docking) has been widely used to discover new ligands based on target structures (Kitchen et al, 2004;Shoichet, 2004;Irwin and Shoichet, 2016;Zhou et al, 2016;Wang et al, 2017;Lyu et al, 2019;Peng et al, 2019). The molecular docking approach is designed to identify small molecules from a large chemical library that possess complementary to a protein binding site.…”

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

“…Beyond the highly conserved amino acid residues localized across the helices either in the proximity of the binding pocket, or participating in the well-established DRY [ 12 ], NpxxY [ 13 ], and P-I-F motifs [ 14 ], or in the conserved disulfide bridge [ 15 ], the most conspicuous differences are present in the extracellular vestibule near the extracellular loop 2 (ECL2) region, which impacts subtype selectivity [ 16 ]. The role of the 5-HT 2B receptor has been implicated in a number of diseases including migraines [ 17 , 18 , 19 ], chronic heart disease [ 20 ], and irritable bowel syndrome (IBS) [ 21 ]. The chemical space of known 5-HT 2B R ligands might be represented by a couple of chemotypes (presented in Figure 1 ).…”

Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists

“…14 A 5HT 2B R antagonist is also under development for irritable bowel syndrome. 18 Therefore, the goal of this study is to discover selective 5HT 2B R antagonists that might have in vivo activities indicative of the potential for disease treatment. This requires deselecting for 5HT 2C R affinity, which is closely associated with 5HT 2B R in the present structural series.…”