Journal Article

Identification of Histamine H 3 Receptor Ligands Using a New Crystal Structure Fragment-based Method

Gloriam, David E, Wellendorph, Petrine, Bräuner-Osborne, Hans, Hauser, Alexander S, Boesgaard, Michael W, Isberg, Vignir, Frandsen, Ida Osborn, Fidom, Kimberley

2017

Overview

Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H receptor with potencies of 0.7-8.5 μM in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.

• Subject: Amino Acid Sequence / Binding Sites / Binding, Competitive / Crystallography, X-Ray / Databases, Pharmaceutical / Gene Expression / HEK293 Cells / High-Throughput Screening Assays / Histamine Agonists - chemistry / Histamine Agonists - metabolism / Histamine Antagonists - chemistry / Histamine Antagonists - metabolism / Humans / Inositol Phosphates - chemistry / Inositol Phosphates - metabolism / Kinetics / Ligands / Methylhistamines - chemistry / Methylhistamines - metabolism / Molecular Docking Simulation / Protein Binding / Protein Conformation, alpha-Helical / Protein Interaction Domains and Motifs / Receptors, Histamine H3 - chemistry / Receptors, Histamine H3 - genetics / Receptors, Histamine H3 - metabolism / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Structure-Activity Relationship / Thermodynamics / User-Computer Interface