Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

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.