Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders
The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhib...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724001149 |
| _version_ | 1827292124212625408 |
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| author | Zhibin Liang Alec Candib David Soriano-Castell Wolfgang Fischer Kim Finley Pamela Maher |
| author_facet | Zhibin Liang Alec Candib David Soriano-Castell Wolfgang Fischer Kim Finley Pamela Maher |
| author_sort | Zhibin Liang |
| collection | DOAJ |
| description | The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds. |
| first_indexed | 2024-04-24T12:51:12Z |
| format | Article |
| id | doaj.art-81892a5e470941209dff8c9ba8004292 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-24T12:51:12Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-81892a5e470941209dff8c9ba80042922024-04-06T04:39:54ZengElsevierRedox Biology2213-23172024-06-0172103138Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disordersZhibin Liang0Alec Candib1David Soriano-Castell2Wolfgang Fischer3Kim Finley4Pamela Maher5Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United States; Corresponding author.Shiley Bioscience Center, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, United StatesCellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United StatesCellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United StatesShiley Bioscience Center, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, United StatesCellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United States; Corresponding author.The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds.http://www.sciencedirect.com/science/article/pii/S2213231724001149CannabinoidDrug discoveryNeurotherapeuticOxytosis/ferroptosisMitochondrial dysfunctionNeurological disorder |
| spellingShingle | Zhibin Liang Alec Candib David Soriano-Castell Wolfgang Fischer Kim Finley Pamela Maher Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders Redox Biology Cannabinoid Drug discovery Neurotherapeutic Oxytosis/ferroptosis Mitochondrial dysfunction Neurological disorder |
| title | Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders |
| title_full | Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders |
| title_fullStr | Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders |
| title_full_unstemmed | Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders |
| title_short | Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders |
| title_sort | fragment based drug discovery and biological evaluation of novel cannabinol based inhibitors of oxytosis ferroptosis for neurological disorders |
| topic | Cannabinoid Drug discovery Neurotherapeutic Oxytosis/ferroptosis Mitochondrial dysfunction Neurological disorder |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724001149 |
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