Human lactate dehydrogenase a inhibitors: a molecular dynamics investigation.
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.
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Yun
Y
Shi
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
B Mario
BM
Pinto
D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008024:Ligands; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5