Pharmacophore Modeling Guided by Conformational Dynamics Reveals Potent Anticancer Agents
In: Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, Jg. 27 (2023), Heft 1, S. 51-63
Online
academicJournal
Zugriff:
Targeting the interaction between tumor suppressor p53 and murine double minute 2(MDM2) has been an attractive therapeutic strategy of recent cancer research. There are a few number of MDM2-targeted anticancer drug molecules undergoing clinical trials, yet none of them have been approved so far. In this study, a new approach is employed in which dynamics of MDM2 obtained by elastic network models are used as a guide in the generation of the ligand-based pharmacophore model prior to virtual screening. Hit molecules exhibiting high affinity to MDM2 were captured and tested by rigid and induced-fit molecular docking. The knowledge of the binding mechanism was used while creating the induced-fit docking criteria. Application of Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method provided an accurate prediction of the binding free energy values. Two leading hit molecules which have shown better docking scores, binding free energy values and drug-like molecular properties were identified. These hits exhibited extra intermolecular interactions with MDM2, indicating a stable complex formation and hence would be further tested in vitro. Finally, the combined computational strategy employed in this study can be a promising tool in drug design for the discovery of potential new hits.
Titel: |
Pharmacophore Modeling Guided by Conformational Dynamics Reveals Potent Anticancer Agents
|
---|---|
Autor/in / Beteiligte Person: | Çarşıbaşı, Nigar |
Link: | |
Zeitschrift: | Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, Jg. 27 (2023), Heft 1, S. 51-63 |
Veröffentlichung: | Suleyman Demirel University, 2023 |
Medientyp: | academicJournal |
ISSN: | 1308-6529 (print) |
DOI: | 10.19113/sdufenbed.1121167 |
Schlagwort: |
|
Sonstiges: |
|