Mechanism-based targeting of lactate dehydrogenase tetramerization by naturally derived compounds: A survey of...

Metabolic reprogramming is a hallmark of cancer, characterized by the upregulation of glycolysis as well as alterations in lactate metabolism via LDH isoforms. LDH is a tetramer formed by two dimers and is commonly overexpressed in tumors. Therefore, targeting LDH tetramerization is a promising therapeutic strategy. We performed molecular docking of over 5000 bioactive compounds from Iranian medicinal plants against four key LDH dimer interface clusters, which are essential for oligomerization. Molecular dynamics simulations of top candidates, along with free LDH dimer, tetramer, and complexes with validated inhibitors, revealed seven compounds with strong inhibitory potential through competitive binding and modulation of dimer dynamics. Notably, Punicafolin from Pomegranate and Myricetin galloyl-hexoxide of Sumac stabilized non-native dimer conformations that prevent normal tetramer formation. Principal component and correlation analyses highlighted the significance of targeting intrinsic dimer flexibility for effective inhibition. Additionally, our QSAR model (R² = 0.8883) demonstrated robust predictive capability for structure-activity relationships of natural LDH inhibitors. These findings support the development of natural-product-based anticancer agents that target metabolic reprogramming through the dynamic regulation of LDH oligomerization.