Identification of antipsychotic drug fluspirilene as a potential p53-MDM2 inhibitor: a combined computational and experimental study
| Autor: | John W. Stoddart, John C. Ruggiero, Kevin S. Gilroy, Joseph M. Notarfrancesco, Joseph J. Butera, Sachin P. Patil, Jonathan D. Griffin, Michael F. Pacitti, Shawn Tran |
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| Rok vydání: | 2014 |
| Předmět: |
Drug
media_common.quotation_subject Fluspirilene Plasma protein binding Molecular Dynamics Simulation Pharmacology Crystallography X-Ray Molecular Docking Simulation Mice chemistry.chemical_compound Drug Discovery medicine Animals Humans Physical and Theoretical Chemistry media_common biology Proto-Oncogene Proteins c-mdm2 Small molecule Computer Science Applications chemistry Docking (molecular) Colonic Neoplasms biology.protein Mdm2 Tumor Suppressor Protein p53 Growth inhibition Protein Binding medicine.drug |
| Zdroj: | Journal of Computer-Aided Molecular Design. 29:155-163 |
| ISSN: | 1573-4951 0920-654X |
| Popis: | 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 % of all human tumor cells. Therefore, pharmacological inhibition of the p53-binding pocket on MDM2, leading to p53 activation, presents an important therapeutic target against these cancers expressing wild-type p53. In this context, the present study utilized an integrated virtual and experimental screening approach to screen a database of approved drugs for potential p53-MDM2 interaction inhibitors. Specifically, using an ensemble rigid-receptor docking approach with four MDM2 protein crystal structures, six drug molecules were identified as possible p53-MDM2 inhibitors. These drug molecules were then subjected to further molecular modeling investigation through flexible-receptor docking followed by Prime/MM-GBSA binding energy analysis. These studies identified fluspirilene, an approved antipsychotic drug, as a top hit with MDM2 binding mode and energy similar to that of a native MDM2 crystal ligand. The molecular dynamics simulations suggested stable binding of fluspirilene to the p53-binding pocket on MDM2 protein. The experimental testing of fluspirilene showed significant growth inhibition of human colon tumor cells in a p53-dependent manner. Fluspirilene also inhibited growth of several other human tumor cell lines in the NCI60 cell line panel. Taken together, these computational and experimental data suggest a potentially novel role of fluspirilene in inhibiting the p53-MDM2 interaction. It is noteworthy here that fluspirilene has a long history of safe human use, thus presenting immediate clinical potential as a cancer therapeutic. Furthermore, fluspirilene could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against several types of cancer. Importantly, the combined computational and experimental screening protocol presented in this study may also prove useful for screening other commercially-available compound databases for identification of novel, small molecule p53-MDM2 inhibitors. |
| Databáze: | OpenAIRE |
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