TY  - JOUR
TI  - Pharmacophore Modeling Guided by Conformational Dynamics Reveals Potent  Anticancer Agents
AB  - 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.
AU  - ÇARSIBASI, NIGAR
DO  - 10.19113/sdufenbed.1121167
PY  - 2023
JO  - Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi
VL  - 27
IS  - 1
SN  - 1300-7688
SP  - 51
EP  - 63
DB  - TRDizin
UR  - http://search/yayin/detay/1164959
ER  -