Modeling G protein-coupled receptors for structure-based drug discovery using low-frequency normal modes for refinement of homology models: Application to H3 antagonists Export

@article{citeulike:5900622, abstract = {G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50\% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low-frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions. Proteins 2010. {\copyright} 2009 Wiley-Liss, Inc.}, address = {Wyeth Research, CN8000, Princeton, New Jersey 08543-8000}, author = {Rai, Brajesh K. and Tawa, Gregory J. and Katz, Alan H. and Humblet, Christine}, citeulike-article-id = {5900622}, citeulike-linkout-0 = {http://dx.doi.org/10.1002/prot.22571}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19787776}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19787776}, citeulike-linkout-3 = {http://www3.interscience.wiley.com/cgi-bin/abstract/122540779/ABSTRACT}, day = {12}, doi = {10.1002/prot.22571}, issn = {1097-0134}, journal = {Proteins: Structure, Function, and Bioinformatics}, keywords = {gpcr, md, modeling, theory}, month = {August}, number = {2}, pages = {457--473}, posted-at = {2009-10-06 19:31:07}, priority = {2}, title = {Modeling G protein-coupled receptors for structure-based drug discovery using low-frequency normal modes for refinement of homology models: Application to H3 antagonists}, url = {http://dx.doi.org/10.1002/prot.22571}, volume = {78}, year = {2010} }

TY - JOUR ID - citeulike:5900622 L3 - citeulike-article-id:5900622 N2 - G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low-frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions. Proteins 2010. © 2009 Wiley-Liss, Inc. IS - 2 JF - Proteins: Structure, Function, and Bioinformatics SN - 1097-0134 AD - Wyeth Research, CN8000, Princeton, New Jersey 08543-8000 EP - 473 TI - Modeling G protein-coupled receptors for structure-based drug discovery using low-frequency normal modes for refinement of homology models: Application to H3 antagonists VL - 78 SP - 457 KW - gpcr KW - md KW - modeling KW - theory AU - Rai, Brajesh AU - Tawa, Gregory AU - Katz, Alan AU - Humblet, Christine PY - 2010/08/12/ UR - http://dx.doi.org/10.1002/prot.22571 ER -