Identification of antipsychotic drug fluspirilene as a potential p53-MDM2 inhibitor: a combined computational and experimental study.

摘要: The inhibition of tumor suppressor p53 protein due to its direct interaction with oncogenic murine double minute 2 (MDM2) protein, plays a central role in almost 50 % all human cells. Therefore, pharmacological the p53-binding pocket on MDM2, leading activation, presents an important therapeutic target against these cancers expressing wild-type p53. In this context, present study utilized integrated virtual and experimental screening approach screen database approved drugs for potential p53-MDM2 inhibitors. Specifically, using ensemble rigid-receptor docking four MDM2 crystal structures, six drug molecules were identified as possible These then subjected further molecular modeling investigation through flexible-receptor followed by Prime/MM-GBSA binding energy analysis. studies fluspirilene, antipsychotic drug, top hit mode similar that native ligand. dynamics simulations suggested stable fluspirilene protein. testing showed significant growth colon cells p53-dependent manner. Fluspirilene also inhibited several other cell lines NCI60 line panel. Taken together, computational data suggest potentially novel inhibiting interaction. It is noteworthy here has long history safe use, thus presenting immediate clinical cancer therapeutic. Furthermore, could serve structurally-novel lead molecule development more potent, small-molecule inhibitors types cancer. Importantly, combined protocol presented may prove useful commercially-available compound databases identification novel, small