Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)

Liu, Tianqi; Jin, Jing; Chen, Yonghui; Xi, Qiumu; Hu, Jiye; Jia, Wen‐Qiang; Chen, Xiaoguang; Li, Yan; Wang, Xiaojian; Yin, Daqiang

doi:10.1016/j.bioorg.2018.09.008

Cited by 3 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The key features of the agonists obtained after these modifications can be summarized as follows: polar head, aromatic region, and lipophilic tail (Liu et al, 2019). Indeed, not only molecules strictly similar to S1P are able to interact with S1P receptors.…”

Section: Fingolimod and Beyondmentioning

confidence: 99%

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

et al. 2019

View full text Add to dashboard Cite

The central nervous system is characterized by a high content of sphingolipids and by a high diversity in terms of different structures. Stage- and cell-specific sphingolipid metabolism and expression are crucial for brain development and maintenance toward adult age. On the other hand, deep dysregulation of sphingolipid metabolism, leading to altered sphingolipid pattern, is associated with the majority of neurological and neurodegenerative diseases, even those totally lacking a common etiological background. Thus, sphingolipid metabolism has always been regarded as a promising pharmacological target for the treatment of brain disorders. However, any therapeutic hypothesis applied to complex amphipathic sphingolipids, components of cellular membranes, has so far failed probably because of the high regional complexity and specificity of the different biological roles of these structures. Simpler sphingosine-based lipids, including ceramide and sphingosine 1-phosphate, are important regulators of brain homeostasis, and, thanks to the relative simplicity of their metabolic network, they seem a feasible druggable target for the treatment of brain diseases. The enzymes involved in the control of the levels of bioactive sphingoids, as well as the receptors engaged by these molecules, have increasingly allured pharmacologists and clinicians, and eventually fingolimod, a functional antagonist of sphingosine 1-phosphate receptors with immunomodulatory properties, was approved for the therapy of relapsing–remitting multiple sclerosis. Considering the importance of neuroinflammation in many other brain diseases, we would expect an extension of the use of such analogs for the treatment of other ailments in the future. Nevertheless, many aspects other than neuroinflammation are regulated by bioactive sphingoids in healthy brain and dysregulated in brain disease. In this review, we are addressing the multifaceted possibility to address the metabolism and biology of bioactive sphingosine 1-phosphate as novel targets for the development of therapeutic paradigms and the discovery of new drugs.

show abstract

Section: Fingolimod and Beyondmentioning

confidence: 99%

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

et al. 2019

View full text Add to dashboard Cite

show abstract

“…38−40 Validation of the Active-Like S1P 1 R Model Based on the Computational and Experimental Approaches. Three compounds containing oxadiazole linker (14a−14c) were selected from Liu et al's manuscript 29 and modified on the polar head and the hydrophobic tail (14d, 13e) to validate the four groups of binding site residues. As depicted in Table 2, all the compounds were evaluated for activity against S1P 1 R in an HTRF-IP1 functional assay.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Three compounds containing oxadiazole linker ( 14a – 14c ) were selected from Liu et al’s manuscript and modified on the polar head and the hydrophobic tail ( 14d , 13e ) to validate the four groups of binding site residues. As depicted in Table , all the compounds were evaluated for activity against S1P 1 R in an HTRF-IP1 functional assay. , The compounds with flexible polar headgroups and electron-deficient aromatic rings were predicted to possess the strongest interactions with S1P 1 R because of the formation of salt bridges with both the guanidyl moiety of Arg120 and the carboxyl moiety of Glu121 and the enhancement of the π–π stacking interactions between the phenyl ring of Phe125 and the electron-deficient aromatic ring on the tail.…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis and Biological Evaluation of Oxadiazole Derivatives. Three compounds (14a−14c, Figure 3) were selected from Liu et al's manuscript, 29 and the compounds with modification on polar head (14d) and hydrophobic tail (13e) were synthesized and subjected to biological evaluations to examine the predicted binding mode of the active-like S1P 1 R with its agonists. The synthetic pathway utilized for the preparation of the oxadiazole derivatives was outlined in Scheme 1.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Computational Approach to the Study of the Binding Mode of S1P₁R Agonists Based on the Active-Like Receptor Model

Chen

Liu

et al. 2019

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Sphingosine-1-phosphate receptor 1 (S1P1R), a member of the G protein-coupled receptor (GPCR) family, is an attractive protein target for the treatment of autoimmune diseases, and a diverse array of S1P1R agonists have been developed. Rational drug design based on S1P1R remains challenging due to the limited information available on the binding mode between S1P1R and its agonists. In this work, the active-like state of S1P1R was modeled via Gaussian accelerated molecular dynamics (GaMD) based on its inactive form, which was further validated by docking studies with two representative S1P1R agonists. Moreover, with the usage of the induced active-like state, the binding mode between S1P1R and its agonists was studied through molecular dynamics simulations and MM-GBSA calculations. The results of those studies indicated that four groups of binding site residues were the major contributors to the ligand and receptor interactions. In addition, this model was verified by five chemically similar compounds synthesized in-house and 1145 known S1P1R agonists collected from the BindingDB database. The elucidation of the key binding characteristics will further complete the cognition of S1P1R, which can guide the rational design of novel S1P1R agonists.

show abstract

Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C H activation of N-oxides

Geyl

Baykov

Tarasenko

et al. 2019

Tetrahedron Letters

View full text Add to dashboard Cite

Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)

Cited by 3 publications

References 34 publications

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

A Computational Approach to the Study of the Binding Mode of S1P₁R Agonists Based on the Active-Like Receptor Model

Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C H activation of N-oxides

Contact Info

Product

Resources

About

Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)

Cited by 3 publications

References 34 publications

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

A Computational Approach to the Study of the Binding Mode of S1P1R Agonists Based on the Active-Like Receptor Model

Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C H activation of N-oxides

Contact Info

Product

Resources

About

A Computational Approach to the Study of the Binding Mode of S1P₁R Agonists Based on the Active-Like Receptor Model