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Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.
- Source :
-
Chemistry & biodiversity [Chem Biodivers] 2019 Jul; Vol. 16 (7), pp. e1900170. Date of Electronic Publication: 2019 Jun 26. - Publication Year :
- 2019
-
Abstract
- The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.<br /> (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)
- Subjects :
- Antineoplastic Agents, Phytogenic chemistry
Antineoplastic Agents, Phytogenic isolation & purification
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
HCT116 Cells
HT29 Cells
Humans
Molecular Conformation
Molecular Dynamics Simulation
Structure-Activity Relationship
Tumor Cells, Cultured
Tumor Suppressor Protein p53 metabolism
Antineoplastic Agents, Phytogenic pharmacology
Drug Discovery
Molecular Docking Simulation
Tumor Suppressor Protein p53 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1612-1880
- Volume :
- 16
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Chemistry & biodiversity
- Publication Type :
- Academic Journal
- Accession number :
- 31134745
- Full Text :
- https://doi.org/10.1002/cbdv.201900170