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Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors.

ABSTRACT: The growing number of studies on G protein-coupled receptors (GPCRs) family are a source of noticeable improvement in our understanding of the functioning of these proteins. GPCRs are responsible for a vast part of signaling in vertebrates and, as such, invariably remain in the spotlight of medicinal chemistry. A deeper insight into the underlying mechanisms of interesting phenomena observed in GPCRs, such as biased signaling or allosteric modulation, can be gained with experimental and computational studies. The latter play an important role in this process, since they allow for observations on scales inaccessible for most other methods. One of the key steps in such studies is proper computational reconstruction of actual ligand-receptor or protein-protein interactions, a process called molecular docking. A number of improvements and innovative applications of this method were documented recently. In this review, we focus particularly on innovations in docking to GPCRs.

SUBMITTER: Bartuzi D

PROVIDER: S-EPMC6155844 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors.

Bartuzi Damian D Kaczor Agnieszka A AA Targowska-Duda Katarzyna M KM Matosiuk Dariusz D

Molecules (Basel, Switzerland) 20170222 2

The growing number of studies on G protein-coupled receptors (GPCRs) family are a source of noticeable improvement in our understanding of the functioning of these proteins. GPCRs are responsible for a vast part of signaling in vertebrates and, as such, invariably remain in the spotlight of medicinal chemistry. A deeper insight into the underlying mechanisms of interesting phenomena observed in GPCRs, such as biased signaling or allosteric modulation, can be gained with experimental and computat ...[more]

PMID: 28241450

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Project description:The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

Project description:Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.

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Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors.

Publications

Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors.

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