Academic Journal
Leveraging the Fragment Molecular Orbital and MM-GBSA Methods in Virtual Screening for the Discovery of Novel Non-Covalent Inhibitors Targeting the TEAD Lipid Binding Pocket
| العنوان: | Leveraging the Fragment Molecular Orbital and MM-GBSA Methods in Virtual Screening for the Discovery of Novel Non-Covalent Inhibitors Targeting the TEAD Lipid Binding Pocket |
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| المؤلفون: | Jongwan Kim, Haiyan Jin, Jinhyuk Kim, Seon Yeon Cho, Sungho Moon, Jianmin Wang, Jiashun Mao, Kyoung Tai No |
| المصدر: | International Journal of Molecular Sciences, Vol 25, Iss 10, p 5358 (2024) |
| بيانات النشر: | MDPI AG |
| سنة النشر: | 2024 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Hippo pathway, TEAD palmitoylation, virtual screening, molecular docking, fragment molecular orbital method, shape-based screening, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | The Hippo pathway controls organ size and homeostasis and is linked to numerous diseases, including cancer. The transcriptional enhanced associate domain (TEAD) family of transcription factors acts as a receptor for downstream effectors, namely yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which binds to various transcription factors and is essential for stimulated gene transcription. YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival. TEAD1–4 overexpression has been observed in different cancers in various tissues, making TEAD an attractive target for drug development. The central drug-accessible pocket of TEAD is crucial because it undergoes a post-translational modification called auto-palmitoylation. Crystal structures of the C-terminal TEAD complex with small molecules are available in the Protein Data Bank, aiding structure-based drug design. In this study, we utilized the fragment molecular orbital (FMO) method, molecular dynamics (MD) simulations, shape-based screening, and molecular mechanics–generalized Born surface area (MM-GBSA) calculations for virtual screening, and we identified a novel non-covalent inhibitor—BC-001—with IC 50 = 3.7 μM in a reporter assay. Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC 50 of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1422-0067 1661-6596 |
| Relation: | https://www.mdpi.com/1422-0067/25/10/5358; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067; https://doaj.org/article/d0dc83c8e7244468a1c95becbdff1b2e |
| DOI: | 10.3390/ijms25105358 |
| الاتاحة: | https://doi.org/10.3390/ijms25105358 https://doaj.org/article/d0dc83c8e7244468a1c95becbdff1b2e |
| رقم الانضمام: | edsbas.B5D2AD13 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14220067 16616596 |
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| DOI: | 10.3390/ijms25105358 |