NMR Screening of mSin3B Binding Compounds for the Interaction Inhibition with a Neural Repressor, NRSF/REST

Kurita, Jun; Hirao, Yuuka; Miyata, Naoki; Nishimura, Yoshifumi

doi:10.1007/978-3-319-28275-6_64-1

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…A microscopic mechanism for the coupled folding and binding of this system was elucidated by our earlier computational study 26 . The NMR work provided a useful strategy for drug discovery: A compound that inhibits the binding of REST/NRSF to the PAH1 cleft of mSin3B can be a potential drug candidate to ameliorate the neuropathies 18 , 27 – 30 , and many compounds have been examined 18 , 22 , 31 .…”

Section: Introductionmentioning

confidence: 99%

Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities

Hayami

Kamiya

Kasahara

et al. 2021

Sci Rep

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A preceding experiment suggested that a compound, which inhibits binding of the REST/NRSF segment to the cleft of a receptor protein mSin3B, can be a potential drug candidate to ameliorate many neuropathies. We have recently developed an enhanced conformational sampling method, genetic-algorithm-guided multi-dimensional virtual-system-coupled canonical molecular dynamics, and in the present study, applied it to three systems consisting of mSin3B and one of three compounds, sertraline, YN3, and acitretin. Other preceding experiments showed that only sertraline inhibits the binding of REST/NRSF to mSin3B. The current simulation study produced the spatial distribution of the compounds around mSin3B, and showed that sertraline and YN3 bound to the cleft of mSin3B with a high propensity, although acitretin did not. Further analyses of the simulation data indicated that only the sertraline–mSin3B complex produced a hydrophobic core similar to that observed in the molecular interface of the REST/NRSF-mSin3B complex: An aromatic ring of sertraline sunk deeply in the mSin3B’s cleft forming a hydrophobic core contacting to hydrophobic amino-acid residues located at the bottom of the cleft. The present study proposes a step to design a compound that inhibits competitively the binding of a ligand to its receptor.

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Section: Introductionmentioning

confidence: 99%

Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities

Hayami

Kamiya

Kasahara

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…A microscopic mechanism for the coupled folding and binding of this system was elucidated by our earlier computational study 26 . The NMR work provided a useful strategy for drug discovery: A compound that inhibits the binding of REST/NRSF to the PAH1 cleft of mSin3B can be a potential drug candidate to ameliorate the neuropathies 18,[27][28][29][30] , and many compounds have been examined 18,22,31 .…”

Section: Introductionmentioning

confidence: 99%

Difference of Binding Modes Among Three Ligands to a Receptor mSin3B Corresponding to Their Inhibitory Activities

Hayami

Kamiya

Kasahara

et al. 2021

Preprint

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A preceding experiment suggested that a compound, which inhibits binding of the REST/NRSF segment to the cleft of a receptor protein mSin3B, can be a potential drug candidate to ameliorate many neuropathies. We have recently developed an enhanced conformational sampling method, genetic-algorithm-guided multi-dimensional virtual-system-coupled canonical molecular dynamics, and in the present study, applied it to three systems consisting of mSin3B and one of three compounds, sertraline, YN3, and acitretin. Other preceding experiments showed that only sertraline inhibits the binding of REST/NRSF to mSin3B. The current simulation study produced the spatial distribution of the compounds around mSin3B, and showed that sertraline and YN3 bound to the cleft of mSin3B with a high propensity, although acitretin did not. Further analyses of the simulation data indicated that only the sertraline–mSin3B complex produced a hydrophobic core similar to that observed in the molecular interface of the REST/NRSF–mSin3B complex: An aromatic ring of sertraline sunk deeply in the mSin3B’s cleft forming a hydrophobic core contacting to hydrophobic amino-acid residues located at the bottom of the cleft. The present study proposes a step to design a compound that inhibits competitively the binding of a ligand to its receptor.

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Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

Kurita

Hirao

Nakano

et al. 2018

Sci Rep

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Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington’s disease, and neuropathic pain. Inhibitors of the interaction between the N-terminal repressor domain of REST/NRSF and the PAH1 domain of its corepressor mSin3 may ameliorate such neuropathies. In-silico screening based on the complex structure of REST/NRSF and mSin3 PAH1 yielded 52 active compounds, including approved neuropathic drugs. We investigated their binding affinity to PAH1 by NMR, and their inhibitory activity toward medulloblastoma cell growth. Interestingly, three antidepressant and antipsychotic medicines, sertraline, chlorprothixene, and chlorpromazine, were found to strongly bind to PAH1. Multivariate analysis based on NMR chemical shift changes in PAH1 residues induced by ligand binding was used to identify compound characteristics associated with cell growth inhibition. Active compounds showed a new chemo-type for inhibitors of the REST/NRSF-mSin3 interaction, raising the possibility of new therapies for neuropathies caused by dysregulation of REST/NRSF.

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NMR Screening of mSin3B Binding Compounds for the Interaction Inhibition with a Neural Repressor, NRSF/REST

Cited by 3 publications

References 39 publications

Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities

Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities

Difference of Binding Modes Among Three Ligands to a Receptor mSin3B Corresponding to Their Inhibitory Activities

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

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