Lactate dehydrogenase (LDH) is an
enzyme that catalyzes the reversible conversion of
lactate to
pyruvate while reducing NAD+ to
NADH (or oxidizing
NADH to
NAD+). Due to its central role in the Warburg effect,
LDH-A isoform has been considered a promising target for treating several types of
cancer. However, research on inhibitors targeting
LDH-B isoform is still limited, despite the
enzyme's implication in the development of specific
cancer types such as breast and
lung cancer. This study aimed to identify small-molecule compounds that specifically inhibit
LDH-B. Our in silico analysis identified eight commercially available compounds that may affect
LDH-B activity. The best five candidates, namely
tucatinib,
capmatinib,
moxidectin,
rifampicin, and acetyldigoxin, were evaluated further in vitro. Our results revealed that two compounds, viz.,
tucatinib and
capmatinib, currently used for treating breast and
lung cancer, respectively, could also act as inhibitors of
LDH-B. Both compounds inhibited
LDH-B activity through an uncompetitive mechanism, as observed in in vitro experiments. Molecular dynamics studies further support these findings. Together, our results suggest that two known drugs currently being used to treat specific
cancer types may have a dual effect and target more than one
enzyme that facilitates the development of these types of
cancers. Furthermore, the results of this study could be used as a new starting point for identifying more potent and specific
LDH-B inhibitors.