Mapping functional group free energy patterns at protein occluded sites: nuclear receptors and G-protein coupled receptors.

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TitleMapping functional group free energy patterns at protein occluded sites: nuclear receptors and G-protein coupled receptors.
Publication TypeJournal Article
Year of Publication2015
AuthorsLakkaraju, SKaushik, Yu, W, E Raman, P, Hershfeld, AV, Fang, L, Deshpande, DA, Mackerell, AD
JournalJ Chem Inf Model
Volume55
Issue3
Pagination700-8
Date Published2015 Mar 23
ISSN1549-960X
KeywordsAdrenergic beta-2 Receptor Antagonists, Animals, Binding Sites, Computer Simulation, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Ligands, Mice, Inbred Strains, Models, Molecular, Molecular Dynamics Simulation, Monte Carlo Method, PPAR gamma, Protein Conformation, Receptors, Adrenergic, beta-2, Receptors, Androgen, Receptors, G-Protein-Coupled, Receptors, Metabotropic Glutamate, Trachea
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.

DOI10.1021/ci500729k
Alternate JournalJ Chem Inf Model
PubMed ID25692383
PubMed Central IDPMC4372819
Grant ListGM051501 / GM / NIGMS NIH HHS / United States
HL104119 / HL / NHLBI NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
R01 GM051501 / GM / NIGMS NIH HHS / United States
R29 GM051501 / GM / NIGMS NIH HHS / United States
R01 AG041265 / AG / NIA NIH HHS / United States
AG041265 / AG / NIA NIH HHS / United States
R01 HL104119 / HL / NHLBI NIH HHS / United States