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Modeling G protein‐coupled receptors for structure‐based drug discovery using low‐frequency normal modes for refinement of homology models: Application to H3 antagonists by Brajesh K. Rai; Gregory J. Tawa; Alan H. Katz; Christine Humblet is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## 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

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

Author

Brajesh K. Rai; Gregory J. Tawa; Alan H. Katz; Christine Humblet

Publisher

John Wiley and Sons; Wiley (John Wiley & Sons); Wiley-Liss Inc; Wiley (ISSN 0887-3585)

Published

2009

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)