Flipping the Target: Evaluating Natural LDHA Inhibitors for Selective LDHB Modulation

Area of Science:

• Biochemistry
• Enzymology
• Pharmacology

Background:

• Lactate dehydrogenase (LDH) interconverts pyruvate and lactate, crucial for cellular metabolism.
• While LDHA is a known cancer target, LDHB's role in cancer metabolic reprogramming is underexplored.
• Existing LDH inhibitors target LDHA's active site, lacking specificity for LDHB.

Purpose of the Study:

• To systematically screen natural compounds for lactate dehydrogenase B (LDHB) inhibition.
• To investigate the isoform-specific inhibitory mechanisms of natural compounds against LDHB.
• To identify novel, selective LDHB inhibitors from natural product libraries.

Main Methods:

• Integrated in silico (virtual screening, molecular docking) and in vitro (enzyme kinetics) approaches.
• Screening of 115 natural compounds previously identified as LDHA inhibitors.
• Utilized a validated colorimetric assay for high-throughput screening.

Main Results:

• Identified 16 lead phytochemicals with LDHB inhibitory potential.
• Luteolin and quercetin demonstrated uncompetitive inhibition of LDHB.
• Molecular docking revealed luteolin and quercetin bind to an allosteric site at the LDHB dimer interface.

Conclusions:

• Luteolin and quercetin exhibit isoform-specific inhibition of LDHB, distinct from LDHA inhibitors.
• Allosteric inhibition of LDHB by natural compounds offers a novel therapeutic strategy.
• This study provides a foundation for designing selective LDHB inhibitors from natural sources.