Prospective virtual screening for novel p53-MDM2 inhibitors using ultrafast shape recognition

J Comput Aided Mol Des. 2014 Feb;28(2):89-97. doi: 10.1007/s10822-014-9732-4. Epub 2014 Feb 20.


The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand-receptor 3D shape complementarity, to screen DrugBank database for novel p53-MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53-MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53-MDM2 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Cell Line, Tumor / drug effects
  • Cell Proliferation / drug effects
  • Databases, Factual
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor / methods*
  • Humans
  • Image Processing, Computer-Assisted / methods*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Ligands
  • Models, Molecular
  • Molecular Docking Simulation
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Prospective Studies
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Telmisartan
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry


  • Benzimidazoles
  • Benzoates
  • Imidazoles
  • Ligands
  • Piperazines
  • Tumor Suppressor Protein p53
  • nutlin 3
  • Proto-Oncogene Proteins c-mdm2
  • Telmisartan