Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line
Glutamate (Glu) toxicity has been an important research topic in toxicology and neuroscience studies. In vitro and in vivo studies have shown that Group II metabotropic Glu2 (mGlu2) activators have cell viability effects. This study aims to determine a candidate ligand with high mGlu2 allosteric reg...
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MDPI AG
2024-01-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/46/1/51 |
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| author | Fadime Canbolat Nigar Kantarci-Carsibasi Sevim Isik Suhair Rami Mohammed Shamshir Münteha Girgin |
| author_facet | Fadime Canbolat Nigar Kantarci-Carsibasi Sevim Isik Suhair Rami Mohammed Shamshir Münteha Girgin |
| author_sort | Fadime Canbolat |
| collection | DOAJ |
| description | Glutamate (Glu) toxicity has been an important research topic in toxicology and neuroscience studies. In vitro and in vivo studies have shown that Group II metabotropic Glu2 (mGlu2) activators have cell viability effects. This study aims to determine a candidate ligand with high mGlu2 allosteric region activity among cytotoxicity-safe molecules using the in silico positioning method and to evaluate its cell viability effect in vitro. We investigated the candidate molecule’s cell viability effect on the SH-SY5Y human neuroblastoma cell line by MTT analysis. In the study, LY 379268 (agonist) and JNJ-46281222 (positive allosteric modulator; PAM) were used as control reference molecules. Drug bank screening yielded THRX-195518 (docking score being −12.4 kcal/mol) as a potential novel drug candidate that has a high docking score and has not been mentioned in the literature so far. The orthosteric agonist LY 379268 exhibited a robust protective effect in our study. Additionally, our findings demonstrate that JNJ-46281222 and THRX-195518, identified as activating the mGlu2 allosteric region through in silico methods, preserve cell viability against Glu toxicity. Therefore, our study not only emphasizes the positive effects of this compound on cell viability against Glu toxicity but also sheds light on the potential of THRX-195518, acting as a mGlu2 PAM, based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) data, as a candidate drug molecule. These findings underscore the potential utility of THRX-195518 against both neurotoxicity and Central Nervous System (CNS) disorders, providing valuable insights. |
| first_indexed | 2024-03-08T11:01:30Z |
| format | Article |
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| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-08T11:01:30Z |
| publishDate | 2024-01-01 |
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| series | Current Issues in Molecular Biology |
| spelling | doaj.art-cf8c27840af140168fb82c319d01bc8f2024-01-26T15:50:59ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452024-01-0146178880710.3390/cimb46010051Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell LineFadime Canbolat0Nigar Kantarci-Carsibasi1Sevim Isik2Suhair Rami Mohammed Shamshir3Münteha Girgin4Department of Pharmacy Services, Vocational School of Health Services, Çanakkale Onsekiz Mart University, 17800 Çanakkale, TurkeyDepartment of Chemical Engineering, Uskudar University, 34662 Istanbul, TurkeyStem Cell Research and Application Center (USKOKMER), Department of Molecular Biology and Genetics, Uskudar University, 34662 Istanbul, TurkeyDepartment of Molecular Biology and Genetics, Uskudar University, 34662 Istanbul, TurkeyDepartment of Chemical Engineering, Uskudar University, 34662 Istanbul, TurkeyGlutamate (Glu) toxicity has been an important research topic in toxicology and neuroscience studies. In vitro and in vivo studies have shown that Group II metabotropic Glu2 (mGlu2) activators have cell viability effects. This study aims to determine a candidate ligand with high mGlu2 allosteric region activity among cytotoxicity-safe molecules using the in silico positioning method and to evaluate its cell viability effect in vitro. We investigated the candidate molecule’s cell viability effect on the SH-SY5Y human neuroblastoma cell line by MTT analysis. In the study, LY 379268 (agonist) and JNJ-46281222 (positive allosteric modulator; PAM) were used as control reference molecules. Drug bank screening yielded THRX-195518 (docking score being −12.4 kcal/mol) as a potential novel drug candidate that has a high docking score and has not been mentioned in the literature so far. The orthosteric agonist LY 379268 exhibited a robust protective effect in our study. Additionally, our findings demonstrate that JNJ-46281222 and THRX-195518, identified as activating the mGlu2 allosteric region through in silico methods, preserve cell viability against Glu toxicity. Therefore, our study not only emphasizes the positive effects of this compound on cell viability against Glu toxicity but also sheds light on the potential of THRX-195518, acting as a mGlu2 PAM, based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) data, as a candidate drug molecule. These findings underscore the potential utility of THRX-195518 against both neurotoxicity and Central Nervous System (CNS) disorders, providing valuable insights.https://www.mdpi.com/1467-3045/46/1/51metabotropic glutamate receptorcell viabilitySH-SY5Ypositive allosteric modulator |
| spellingShingle | Fadime Canbolat Nigar Kantarci-Carsibasi Sevim Isik Suhair Rami Mohammed Shamshir Münteha Girgin Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line Current Issues in Molecular Biology metabotropic glutamate receptor cell viability SH-SY5Y positive allosteric modulator |
| title | Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line |
| title_full | Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line |
| title_fullStr | Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line |
| title_full_unstemmed | Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line |
| title_short | Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line |
| title_sort | identification of the candidate mglu2 allosteric modulator thrx 195518 through in silico method and evaluation of its neuroprotective potential against glutamate induced neurotoxicity in sh sy5y cell line |
| topic | metabotropic glutamate receptor cell viability SH-SY5Y positive allosteric modulator |
| url | https://www.mdpi.com/1467-3045/46/1/51 |
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