Pharmacophore Modeling Guided by Conformational Dynamics Reveals Potent Anticancer Agents

Authors : Nigar ÇARŞIBAŞI

Pages : 51-63

Doi:10.19113/sdufenbed.1121167

View : 23 | Download : 23

Publication Date : 2023-04-25

Article Type : Research Paper

Abstract :Targeting the interaction between tumor suppressor p53 and murine double minute 2insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(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.
Keywords : elastik ağ modeli, ilaç yeniden konumlandırma, uyarılmış uyumlu moleküler yerleştirme, MDM2, p53