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Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcholine receptors. Our results indicate that unlike synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket. We also discovered that the most recently resolved crystal structure of the LTB4 receptor comprised a bound inverse agonist, which extended its benzamidine moiety to the same binding pocket discovered in this work. Analysis on all resolved GPCR crystal structures indicated that this new pocket could exist in most receptors. Our findings provide new opportunities for GPCR drug discovery.
Pubmed ID: 30310578
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Collection of information about chemical structures and biological properties of small molecules and siRNA reagents hosted by the National Center for Biotechnology Information (NCBI).
View all literature mentionsA vector graphics software which runs on Windows, Mac OS X and GNU/Linux. It can import and export various file formats, including SVG, AI, EPS, PDF, PS and PNG. Features include object creation, object manipulation, color editing, and text editing.
View all literature mentionsCommercial ogranization which provides molecular and drug discovery software and services to researchers. American software company that develops chemical simulation software for use in pharmaceutical, biotechnology, and materials science research. Provides products ranging from general molecular modeling programs to a full suite of chemical simulation and drug design software, including ligand- and structure-based methods.
View all literature mentionsSoftware program for electronic structure modeling that enables researchers to study and predict the properties of molecules and reactions under a wide range of conditions, especially those that are difficult or impossible to observe experimentally.
View all literature mentionsSoftware for predicting protein ligand binding sites that integrate evolutionary sequence conservation estimates with structure-based methods for identifying protein surface cavities. Used in predicting catalytic sites and drug binding pockets.
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
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