Virtual high-throughput screens identifying hPK-M2 inhibitors: Exploration of model extrapolation

Area of Science:

• Biochemistry
• Oncology
• Computational Chemistry

Background:

• The Warburg effect, or aerobic glycolysis, is a hallmark of cancer, providing energy and biomass for tumor growth.
• Human pyruvate kinase M2 (hPK-M2) is a key enzyme in glycolysis and a potential therapeutic target in oncogenesis.

Purpose of the Study:

• To identify novel inhibitors of human PK-M2 (hPK-M2) using virtual high-throughput screening.
• To discover new chemical scaffolds for anti-cancer drug development targeting the Warburg effect.

Main Methods:

• Virtual high-throughput screening of chemical compounds targeting hPK-M2.
• Experimental validation of selected candidates from initial and retrained models.
• Analysis of identified chemical scaffolds for further drug discovery efforts.

Main Results:

• The initial virtual screen yielded a hit rate of 8.13% for experimental validation.
• A second screen using retrained models achieved a significantly improved hit rate of 54.5%.
• Four distinct chemical scaffolds were identified for potential therapeutic development.

Conclusions:

• Virtual screening is an effective strategy for identifying hPK-M2 inhibitors.
• The identified scaffolds represent promising starting points for developing novel anti-cancer therapeutics targeting the Warburg effect.
• Stepwise extrapolation in screening can enhance efficiency and discovery.