Related Experiment Video
Updated: Oct 29, 2025
Live-cell Measurement of Odorant Receptor Activation Using a Real-time cAMP Assay
Published on: October 2, 2017
A two-stage computational approach to predict novel ligands for a chemosensory receptor
Amara Jabeen1, Ramya Vijayram2, Shoba Ranganathan1
1Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Abstract:
Olfactory receptor (OR) 1A2 is the member of largest superfamily of G protein-coupled receptors (GPCRs). OR1A2 is an ectopically expressed receptor with only 13 known ligands, implicated in reducing hepatocellular carcinoma progression, with enormous therapeutic potential. We have developed a two-stage screening approach to identify novel putative ligands of OR1A2. We first used a pharmacophore model based on atomic property field (APF) to virtually screen a library of 5942 human metabolites. We then carried out structure-based virtual screening (SBVS) for predicting the potential agonists, based on a 3D homology model of OR1A2. This model was developed using a biophysical approach for template selection, based on multiple parameters including hydrophobicity correspondence, applied to the complete set of available GPCR structures to pick the most appropriate template. Finally, the membrane-embedded 3D model was refined by molecular dynamics (MD) simulations in both the apo and holo forms. The refined model in the apo form was selected for SBVS. Four novel small molecules were identified as strong binders to this olfactory receptor on the basis of computed binding energies.
Insights
Researchers identified novel small molecules that bind to olfactory receptor 1A2 (OR1A2), a G protein-coupled receptor (GPCR) with therapeutic potential for hepatocellular carcinoma.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Olfactory receptor 1A2 (OR1A2), a G protein-coupled receptor (GPCR), is ectopically expressed and linked to reduced hepatocellular carcinoma progression.
- OR1A2 has a limited number of known ligands, indicating a need for novel ligand discovery.
Purpose of the Study:
- To identify novel putative ligands for the olfactory receptor 1A2 (OR1A2).
- To explore the therapeutic potential of OR1A2 ligands in treating hepatocellular carcinoma.
Main Methods:
- A two-stage virtual screening approach was employed, beginning with pharmacophore modeling using atomic property field (APF) on human metabolites.
- Structure-based virtual screening (SBVS) was performed using a refined 3D homology model of OR1A2, developed via biophysical template selection and molecular dynamics (MD) simulations.
Main Results:
- Four novel small molecules were identified as potent binders to OR1A2 based on computed binding energies.
- The study successfully screened a library of 5942 human metabolites.
Conclusions:
- The identified small molecules represent potential therapeutic agents targeting OR1A2 for hepatocellular carcinoma treatment.
- This study demonstrates a robust computational strategy for discovering ligands for olfactory receptors.
More Related Videos
Related Concept Videos
02:40Ligand Binding Sites
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
01:29The Two-State Receptor Model
The binding affinity of a drug determines its interaction with...
01:15G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...