Screening of novel inhibitors targeting lactate dehydrogenase A via four molecular docking strategies and dynamics simulations.

Lactate dehydrogenase A (LDHA) is a metabolic enzyme which catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway, thus playing key roles in aerobic glycolysis. The inhibition of LDHA by small molecules has become an attractive strategy for anticancer therapy in recent years. However, very few LDHA inhibitors have been reported, even though a great deal of effort has directed into identifying LDHA inhibitors using structure-based approaches. Therefore, high-throughput and high-accuracy screening approaches are still urgently needed in order to target LDHA effectively. In the present work, after establishing that our docking strategies performed well using test datasets, we screened 32791 Specs products for their docking scores with the substrate-binding pocket and, separately, the cofactor-binding pocket of LDHA. We subsequently identified 76 hits (i.e., ligands that show low docking scores) for the cofactor-binding pocket and 27 hits for the substrate-binding pocket. Two representative compounds, ZINC20036549 and ZINC19369718, were then chosen for further MD simulation analysis, and we found that these compounds maintained their inhibitory activity during the MD simulations. Meanwhile, we found that ZINC19369718 interacts with a novel binding site close to the active site, and that this interaction may inhibit the catalytic activity of LDHA. Together, these results offer not only a new paradigm for identifying Specs drug-like products for novel therapeutic use but they also provide further opportunity to adopt LDHA inhibition as a strategy for cancer therapy.