Knowledge-driven design and optimization of potent symmetric anticancer molecules: A case study on PKM2 activators

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Pyruvate kinase M2 (PKM2) is a key enzyme in cancer metabolism, often existing as a low-activity dimer in proliferating tumor cells.
• This altered PKM2 state promotes metabolic reprogramming, fueling uncontrolled tumor growth by shifting from the normal glycolytic pathway.
• Targeting PKM2 offers a potential strategy to restore normal metabolism and inhibit tumor progression.

Purpose of the Study:

• To utilize knowledge-based drug discovery to identify critical features of known PKM2 activators.
• To design novel compounds with improved structural and functional properties for PKM2 activation.
• To develop potential therapeutic agents that stabilize the active tetrameric form of PKM2.

Main Methods:

• Molecular modeling studies were performed to identify critical structural features of PKM2 activators.
• A virtual library of 200 activators was designed based on these features to target a specific binding site.
• Designed compounds underwent pharmacokinetic profiling, toxicity prediction, binding energy calculations, and molecular dynamics (MD) simulations.

Main Results:

• All designed activators exhibited high binding affinities to PKM2, ranging from -9.1 to -15.0 kcal/mol.
• The compounds demonstrated favorable pharmacokinetic profiles and predicted toxicity.
• MD simulations confirmed that the best activators stabilize the desired tetrameric conformation of PKM2.

Conclusions:

• The designed PKM2 activators possess high binding affinities and favorable drug-like properties.
• These compounds effectively stabilize the tetrameric conformation of PKM2, suggesting potential therapeutic applications.
• Targeting PKM2 tetramerization could restore normal glycolysis and suppress tumor progression.