Abstract
Lactate dehydrogenase A (LDHA) is an important enzyme in fermentative glycolysis, generating most energy for cancer cells that rely on anaerobic respiration even under normal oxygen concentrations. This renders LDHA a promising molecular target for the treatment of various cancers. Several efforts have been made recently to develop LDHA inhibitors with nanomolar inhibition and cellular activity, some of which have been studied in complex with the enzyme by X-ray crystallography. In this work, we present a molecular dynamics (MD) study of the binding interactions of selected ligands with human LDHA. Conventional MD simulations demonstrate different binding dynamics of inhibitors with similar binding affinities, whereas steered MD simulations yield discrimination of selected LDHA inhibitors with qualitative correlation between the in silico unbinding difficulty and the experimental binding strength. Further, our results have been used to clarify ambiguities in the binding modes of two well-known LDHA inhibitors.
Highlights
An emerging hallmark of cancer is its altered cell energy metabolism that favors anaerobic respiration over aerobic respiration. [1,2] Unlike normal cells that utilize the Krebs cycle as the major energy-producing process in the presence of adequate oxygen, many cancer cells preferentially derive ATP through glycolysis, followed by fermentation that converts pyruvate to lactate
Conventional molecular dynamics (MD) simulations were performed in triplicate for each system of human Lactate dehydrogenase A (LDHA):ligand complex for 60 ns
For LDHA:PYR-NADH, LDHA:2B4, and LDHA:NHIS, only chains A, B, and C were analyzed since these systems were shown to prefer a loop-closed conformation (Table 2) while the loop in chain D stayed open
Summary
An emerging hallmark of cancer is its altered cell energy metabolism that favors anaerobic respiration over aerobic respiration. [1,2] Unlike normal cells that utilize the Krebs cycle as the major energy-producing process in the presence of adequate oxygen, many cancer cells preferentially derive ATP through glycolysis, followed by fermentation that converts pyruvate to lactate. [7] human LDHA could be a molecular target for the inhibition of fermentative glycolysis and the growth and proliferation of cancer cells. It is required for the initiation, maintenance, and progression of tumors. Human LDHA has a tetrameric structure with four identical monomers, each in possession of its own NADH cofactor binding site and substrate binding site (Figure 1A). [17] Yet, the first human LDHA structure (PDB 1I10), in complex with a substrate mimic (oxamate) and the cofactor NADH, shows that the mobile loop of one of the four identical monomers, chain D, is in an open conformation, indicating certain probability of the loop being open. There have been several efforts to develop human LDHA inhibitors, [15,18,19,20,21] and crystal structures are available for complexes of some inhibitors and LDHAs from human, rat, and rabbit. [18,19,20,21] A fragment-based approach has been successfully employed to combine adenosine-site (A-site) binders and nicotinamide/substrate-site (S-site) binders, yielding dual-site binders with nanomolar binding affinities (Figure 2 and Table 1). [18,19]
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