Structural basis for σ1 receptor ligand recognition

Schmidt, Hayden R.; Betz, Robin M.; Dror, Ron O.; Kruse, Andrew C.

doi:10.1038/s41594-018-0137-2

Cited by 119 publications

(211 citation statements)

References 60 publications

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“…After their chemoinformatic assignment to the Sigma1 receptor, cloperastine and clemastine were docked into the agonist-bound state structure of the receptor (6DK1) 79 using DOCK3.7 80 . The best scoring configurations that ion-pair with Glu172 are shown; both l-cloperastine and clemastine receive solvation-corrected docking scores between −42 and −43 kcal/mol, indicating high complementarity.…”

Section: Methodsmentioning

confidence: 99%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

3,913

157

5,576

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The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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Section: Methodsmentioning

confidence: 99%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

3,913

157

5,576

View full text Add to dashboard Cite

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“…Despite its physiological and pharmacological significance, the structure-function relationships of σ1R are poorly understood. The recent crystal structures of σ1R in complexes with a variety of ligands provide the foundation for mechanistic elucidation of its function at the molecular level (Schmidt et al, 2016(Schmidt et al, , 2018. They shed light on the conformation and homomeric status of σ1R in the membrane environment.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Terminal Tagging on Homomeric Interactions of the Sigma 1 Receptor

et al. 2019

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The sigma 1 receptor (σ1R) has been implicated in cancers, neurological disorders, and substance use disorders. Yet, its molecular and cellular functions have not been well-understood. Recent crystal structures of σ1R reveal a single N-terminal transmembrane segment and C-terminal ligand-binding domain, and a trimeric organization. Nevertheless, outstanding issues surrounding the functional or pharmacological relevance of σ1R oligomerization remain, such as the minimal protomeric unit and the differentially altered oligomerization states by different classes of ligands. Western blot (WB) assays have been widely used to investigate protein oligomerizations. However, the unique topology of σ1R renders several intertwined challenges in WB. Here we describe a WB protocol without temperature denaturization to study the ligand binding effects on the oligomerization state of σ1R. Using this approach, we observed unexpected ladder-like incremental migration pattern of σ1R, demonstrating preserved homomeric interactions in the detergent environment. We compared the migration patterns of intact σ1R construct and the C-terminally tagged σ1R constructs, and found similar trends in response to drug treatments. In contrast, N-terminally tagged σ1R constructs show opposite trends to that of the intact construct, suggesting distorted elicitation of the ligand binding effects on oligomerization. Together, our findings indicate that the N-terminus plays an important role in eliciting the impacts of bound ligands, whereas the C-terminus is amenable for modifications for biochemical studies.

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“…The designed library consists of six different ketones reported in Figure 5 . This compound library still maintains the structural features needed to interact with S1Rs, namely the basic nitrogen and the hydrophobic moieties [ 23 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

Rossino

Rui

Pozzetti

et al. 2020

IJMS

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Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method was validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood–brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-D-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1’-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.

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Structural basis for σ1 receptor ligand recognition

Cited by 119 publications

References 60 publications

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The Effects of Terminal Tagging on Homomeric Interactions of the Sigma 1 Receptor

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

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