Virtual screening using covalent docking to find activators for G245S mutant p53

Area of Science:

• Oncology
• Computational Chemistry
• Drug Discovery

Background:

• The TP53 gene is frequently mutated in cancer, leading to a non-functional mutant p53 protein.
• Reactivating mutant p53 is a key strategy for developing novel anti-cancer therapies.
• Current methods for identifying mutant p53 reactivators are limited.

Purpose of the Study:

• To identify novel small molecules capable of reactivating the G245S-mutant p53 protein using in silico screening.
• To evaluate the drug-like properties and potential toxicities of identified compounds.

Main Methods:

• In silico screening of the ZINC15 database (13 million compounds) against G245S-mutant p53.
• Filtering for drug-like molecules with moderate to standard reactivity.
• Covalent docking at C124 of G245S-mutant p53 using the DOCKTITE protocol.
• Compound ranking using consensus scoring and ADMET prediction.

Main Results:

• Identification of potential G245S-mutant p53 activators, primarily thiosemicarbazones and halo-carbonyls.
• Compound 2 demonstrated the highest potential as a G245S-mutant p53 activator based on binding and ADMET risk scores.
• The screening successfully filtered a large chemical library to identify promising drug candidates.

Conclusions:

• In silico screening is an effective method for discovering novel mutant p53 reactivators.
• Compound 2 represents a promising lead for further development as an anti-cancer therapeutic targeting G245S-mutant p53.
• This study provides a foundation for developing targeted therapies against TP53-mutated cancers.