(1096) Exploration of the Thermodynamics of the Surface Water Molecules for the Discovery of Novel LDHA Inhibitors

Objectives: Lactate dehydrogenase-A (LDH-A) is upregulated in most tumors and executes the last step of aerobic glycolysis by catalyzing the conversion of pyruvate to lactic acid. Although some LDHA inhibitors are known in the literature, only a few have been shown to possess cellular activity. Further, the development of these molecules has been hampered either because they contain some reactive functional groups, lack drug-like properties, or the structure was metabolically susceptible, leading to poor pharmacokinetic profile. The goal of this study is to conduct virtual screening using computational approaches to identify novel molecules against LDH-A for cancer therapy.

Methods: In our study, we performed a virtual screening of the ZINC database containing 16 million virtual compounds and employed WaterMap to determine the thermodynamic properties, including the entropy, enthalpy, and free energy of crystallographic water molecules in the LDHA binding site.

Results: We determined key hydration sites on the protein surface that are energetically unfavorable and identified amino acids that could be targeted for ligand binding.

Conclusions: WaterMap revealed key amino acids in the LDH-A binding site, that could be important for potency. We used this information in our virtual screening campaign to prioritize compounds for biological screening in LDH-A inhibition assays. Out of 29 compounds we tested 17 hits showed a moderate to potent inhibition ofLDH-A. The two most potent hits discovered from virtual screening also inhibited pancreatic cancer cell lines in low micromolar concentrations.