Structure versus function—The impact of computational methods on the discovery of specific GPCR–ligands

Bermudez, Marcel; Wolber, Gerhard

doi:10.1016/j.bmc.2015.03.026

Cited by 24 publications

(21 citation statements)

References 72 publications

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“…forming a ligand binding ensemble, we here apply an interdisciplinary approach combining molecular modeling techniques guided by pharmacological experiments and vice versa. Our modeling strategy consists of a combination of allatom molecular dynamics (MD) simulations and three-dimensional pharmacophores (36,37).…”

Section: Direct Pharmacological Evidence For Multiple Bindingmentioning

confidence: 99%

“…Docking, All-atom Molecular Dynamics Simulations, and Three-dimensional Pharmacophore Analysis-In the presented study, different modeling techniques, such as docking, all-atom MD simulations, and both static and dynamic three-dimensional pharmacophore analyses, were successfully combined (36). All protein-ligand docking experiments reported in this study were carried out with the Cambridge Crystallographic Data Centre's software GOLD version 5.1 (61).…”

Section: Site-directed Mutagenesis and Generation Of Stable Cellmentioning

confidence: 99%

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Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Böck

Bermudez

Krebs

et al. 2016

Journal of Biological Chemistry

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G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood.Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M 2 receptors to demonstrate the existence and function of such inactive agonist⅐receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist⅐receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist⅐receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.Specific and coordinated cell-to-cell communication regulates the flow of information between cells, and proper information processing ensures physiological functions of biological systems. G protein-coupled receptors (GPCRs), 8 constituting the largest class of membrane proteins in mammals, are essential mediators of chemically and light-encoded information (1-4). GPCRs sense a great variety of extracellular stimuli, e.g. neurotransmitters and hormones, and subsequently translate this information into an intracellular response via G proteins, ␤-arrestins, and possibly GPCR-interacting proteins (2-5). Because of their abundance and relevance in regulating the majority of (patho-)physiological processes in humans, GPCRs have for a long time represented the most important drug targets being addressed by at least a third of all currently marketed drugs (6, 7).Agonist binding leads to receptor activation, which is followed by intracellular G protein recruitment and subsequent cell signaling. Breakthroughs in GPCR crystallography have led to inactive and active crystal structures of the same receptor protein. Among these are rhodopsin (8 -10) and more recently the ␤ 2 -adrenergic (11-14), M 2 muscarinic (15, 16), and -opioid receptors (17, 18). These structures most likely represent energetically favored, relatively stable inactive and active receptor⅐ligand complexes. Despite the diversity of crystallized receptors, a common...

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Section: Direct Pharmacological Evidence For Multiple Bindingmentioning

confidence: 99%

Section: Site-directed Mutagenesis and Generation Of Stable Cellmentioning

confidence: 99%

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Böck

Bermudez

Krebs

et al. 2016

Journal of Biological Chemistry

Self Cite

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show abstract

“…These have been reviewed more extensively. In a recent review [103], the authors summarize recent examples of successful in silico structural and functional investigations of GPCR proteins, the rationalization of binding modes of GPCR ligands, GPCR binding-site identification, and the development of novel GPCR ligands. The computational methods that facilitated the computational chemistry successes included molecular dynamics, pharmacophore modeling, virtual screening, construction and utilization of homology models, and de novo ligand design.…”

Section: Computational Drug-discovery Studiesmentioning

confidence: 99%

The role of experimental and computational structural approaches in 7TM drug discovery

Topiol¹,

Sabio²

2015

Expert Opinion on Drug Discovery

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There is now a significant amount of structural information covering a range of 7TM protein classes (A, B, C, and F) and activation states. For these and closely related proteins, structure-based drug discovery has proven to be a powerful tool. More structural information is needed with respect to dimerization, 7TM proteins with β-arrestin to help in understanding the control of biased signaling, and full-protein structure determinations for non-class A proteins to help in understanding and controlling their functioning. Finally, the use of the existing structural information to target new sites on these proteins needs further exploration.

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“…In general, due to the better understanding of various receptor states and the multiple signalling roles of GPCRs, the discovery of tailored ligands will gain more and more relevance. Computational techniques such as virtual screening and de novo design can help in the discovery process (Figure ) …”

Section: Exploitation Of the Conformational Space Of Gpcrs For Drug mentioning

confidence: 99%

In silicoExploration of the Conformational Universe of GPCRs

2016

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The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design.

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Structure versus function—The impact of computational methods on the discovery of specific GPCR–ligands

Cited by 24 publications

References 72 publications

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

The role of experimental and computational structural approaches in 7TM drug discovery

In silicoExploration of the Conformational Universe of GPCRs

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