1. A two-stage computational approach to predict novel ligands for a chemosensory receptor
- Author
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Amara Jabeen, Ramya Vijayram, and Shoba Ranganathan
- Subjects
Hydrophobicity correspondence ,MD, Molecular dynamics ,Virtual ligand screening ,SSD, Sum of squared difference ,HMDB, Human metabolome database ,Atomic property field ,Binding free energy calculation ,Computational biology ,Molecular dynamics ,RMSF, Root mean square fluctuation ,PMEMD, Particle-Mesh Ewald Molecular Dynamics ,Article ,RMSD, Root mean square deviation ,MMGBSA, Molecular mechanics generalized born surface area ,Structural Biology ,LBVS, Ligand based virtual screening ,medicine ,Olfactory receptor ,Homology modeling ,Receptor ,Molecular Biology ,lcsh:QH301-705.5 ,G protein-coupled receptor ,HCMV, Human cytomegalovirus ,Virtual screening ,CSF, Cerebrospinal fluid ,Chemistry ,LC, Lung carcinoids ,ECL, Extracellular loop ,NAFLD, Non-alcoholic fatty liver disease ,Small molecule ,GPCR, G protein coupled receptor ,APF, Atomic property field ,MMPBSA, Molecular mechanics Poisson–Boltzmann surface area ,medicine.anatomical_structure ,lcsh:Biology (General) ,OR, olfactory receptor ,POPC, 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphatidylcholine ,Pharmacophore ,OR1A2 ,SBVS, Structure based virtual screening ,Amber, Assisted model Building with Energy Refinement ,TM, Transmembrane ,NASH, Nonalcoholic steatohepatitis - 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., Graphical abstract Image 1, Highlights • A two-stage screening has led to the prediction of structurally similar ligands for OR1A2. • A biophysical approach, including a novel parameter of hydrophobicity correspondence, is presented for template selection. • Available GPCR templates for OR1A2 have been comprehensively compared using our proposed biophysical approach. • 1U19 is suggested to be the best template for OR1A2 on the basis of biophysical properties. • Combining ligand-based and structure-based screening might facilitate decoding of ORs molecular receptive code.
- Published
- 2020