Molecular modelling of human 5-hydroxytryptamine receptor (5-HT2A) and virtual screening studies towards the identification of agonist and antagonist molecules

J Biomol Struct Dyn. 2016 May;34(5):952-70. doi: 10.1080/07391102.2015.1062802. Epub 2015 Sep 1.


The serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels found in the central and peripheral nervous systems. GPCRs have a characteristic feature of activating different signalling pathways upon ligand binding and these ligands display several efficacy levels to differentially activate the receptor. GPCRs are primary drug targets due to their central role in several signal transduction pathways. Drug design for GPCRs is also most challenging due to their inherent promiscuity in ligand recognition, which gives rise to several side effects of existing drugs. Here, we have performed the ligand interaction study using the two prominent states of GPCR, namely the active and inactive state of the 5-HT2A receptor. Active state of 5-HT2A receptor model enhances the understanding of conformational difference which influences the ligand-binding site. A 5-HT2A receptor active state model was constructed by homology modelling using active state β2-adrenergic receptor (β2-AR). In addition, virtual screening and docking studies with both active and inactive state models reveal potential small molecule hits which could be considered as agonist-like and antagonist-like molecules. The results from the all-atom molecular dynamics simulations further confirmed that agonists and antagonists interact in different modes with the receptor.

Keywords: 5-HT2A receptor; agonist; antagonist; induced fit docking; molecular dynamics; scaffold similarity; virtual screening.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Drug Discovery*
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Receptors, Serotonin, 5-HT2 / chemistry*
  • Reproducibility of Results
  • Serotonin 5-HT2 Receptor Agonists / chemistry*
  • Serotonin 5-HT2 Receptor Antagonists / chemistry*


  • Ligands
  • Receptors, Serotonin, 5-HT2
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists