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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery

Xin Li1, Xin-Xin Zhang2, Yu-Xi Lin1

  • 1School of Life Science, Lanzhou University, Lanzhou, 730000, P. R. China.

Chemistry & Biodiversity
|May 29, 2019
PubMed

Insights

Torilin, a natural product, activates wild-type p53 tumor suppressor function by targeting the Loop1/Sheet3 pocket. This leads to increased p21 expression and suppressed HCT116 cancer cell growth.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • The tumor suppressor p53 is a key drug target, with research focusing on stabilizing functional p53 or reactivating mutated p53.
  • Small molecules targeting the Loop1/Sheet3 (L1/S3) pocket have shown potential in reactivating mutant p53 and stabilizing wild-type p53 in vitro.

Purpose of the Study:

  • To identify natural products that target the L1/S3 pocket of wild-type (WT) p53.
  • To investigate the potential of identified compounds in suppressing cancer cell growth through p53 activation.

Main Methods:

  • Virtual screening of natural products against the L1/S3 pocket of WT p53.
  • Utilized ensemble docking with seven conformations to account for Loop1 flexibility.
  • Assessed p53 activity, p21 protein expression, and HCT116 cancer cell growth suppression.

Main Results:

  • Torilin was identified as a promising candidate from 181 screened compounds.
  • Torilin enhanced p53 activity and increased downstream p21 protein expression.
  • Torilin suppressed HCT116 cancer cell growth, potentially through covalent binding to Cys124 via its 2-methyl-2-butenal (2M2B) group.

Conclusions:

  • The L1/S3 pocket of WT-p53 is a druggable target.
  • Torilin exhibits potential cytotoxicity by activating the p53 pathway.
  • The 2M2B group in torilin appears crucial for its p53-activating activity.
Keywords:
anticancercytotoxicitydrug discoveryp53torilinvirtual screening

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