Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities
Abstract 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-algo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-85612-9 |
| _version_ | 1818460361764896768 |
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| author | Tomonori Hayami Narutoshi Kamiya Kota Kasahara Takeshi Kawabata Jun-ichi Kurita Yoshifumi Fukunishi Yoshifumi Nishimura Haruki Nakamura Junichi Higo |
| author_facet | Tomonori Hayami Narutoshi Kamiya Kota Kasahara Takeshi Kawabata Jun-ichi Kurita Yoshifumi Fukunishi Yoshifumi Nishimura Haruki Nakamura Junichi Higo |
| author_sort | Tomonori Hayami |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-14T23:29:02Z |
| format | Article |
| id | doaj.art-2898f8cc3360474e8e56e88ebf1a1694 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T23:29:02Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2898f8cc3360474e8e56e88ebf1a16942022-12-21T22:43:44ZengNature PortfolioScientific Reports2045-23222021-03-0111111210.1038/s41598-021-85612-9Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activitiesTomonori Hayami0Narutoshi Kamiya1Kota Kasahara2Takeshi Kawabata3Jun-ichi Kurita4Yoshifumi Fukunishi5Yoshifumi Nishimura6Haruki Nakamura7Junichi Higo8Institute for Protein Research, Osaka UniversityGraduate School of Simulation Studies, University of HyogoCollege of Life Sciences, Ritsumeikan UniversityInstitute for Protein Research, Osaka UniversityGraduate School of Medical Life Science, Yokohama City UniversityCellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)Graduate School of Medical Life Science, Yokohama City UniversityInstitute for Protein Research, Osaka UniversityInstitute for Protein Research, Osaka UniversityAbstract 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.https://doi.org/10.1038/s41598-021-85612-9 |
| spellingShingle | Tomonori Hayami Narutoshi Kamiya Kota Kasahara Takeshi Kawabata Jun-ichi Kurita Yoshifumi Fukunishi Yoshifumi Nishimura Haruki Nakamura Junichi Higo Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities Scientific Reports |
| title | Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities |
| title_full | Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities |
| title_fullStr | Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities |
| title_full_unstemmed | Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities |
| title_short | Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities |
| title_sort | difference of binding modes among three ligands to a receptor msin3b corresponding to their inhibitory activities |
| url | https://doi.org/10.1038/s41598-021-85612-9 |
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