title: Mapping functional group free energy patterns at protein occluded sites: nuclear receptors and G-protein coupled receptors.
abstract: Occluded ligand-binding pockets (LBP) such as those found in nuclear receptors (NR) and G-protein coupled receptors (GPCR) represent a significant opportunity and challenge for computer-aided drug design. To determine free energies maps of functional groups of these LBPs, a Grand-Canonical Monte Carlo/Molecular Dynamics (GCMC/MD) strategy is combined with the Site Identification by Ligand Competitive Saturation (SILCS) methodology. SILCS-GCMC/MD is shown to map functional group affinity patterns that recapitulate locations of functional groups across diverse classes of ligands in the LBPs of the androgen (AR) and peroxisome proliferator-activated-γ (PPARγ) NRs and the metabotropic glutamate (mGluR) and β2-adreneric (β2AR) GPCRs. Inclusion of protein flexibility identifies regions of the binding pockets not accessible in crystal conformations and allows for better quantitative estimates of relative ligand binding affinities in all the proteins tested. Differences in functional group requirements of the active and inactive states of the β2AR LBP were used in virtual screening to identify high efficacy agonists targeting β2AR in Airway Smooth Muscle (ASM) cells. Seven of the 15 selected ligands were found to effect ASM relaxation representing a 46% hit rate. Hence, the method will be of use for the rational design of ligands in the context of chemical biology and the development of therapeutic agents.
authors.forename: Sirish Kaushik
authors.initials: SK
authors.lastname: Lakkaraju
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.forename: E Prabhu
authors.initials: EP
authors.lastname: Raman
authors.forename: Alena V
authors.initials: AV
authors.lastname: Hershfeld
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: §Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, United States.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
chemical_list: C410798:AR protein, human; D058672:Adrenergic beta-2 Receptor Antagonists; D008024:Ligands; D047495:PPAR gamma; D018343:Receptors, Adrenergic, beta-2; D011944:Receptors, Androgen; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate