Human Lactate Dehydrogenase A Inhibitors: A Molecular Dynamics Investigation

Resource type
Date created
2014-01-17
Authors/Contributors
Author: Shi, Yun
Author: Pinto, Mario
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.
Document
Published as
Shi Y, Pinto BM (2014) Human Lactate Dehydrogenase A Inhibitors: A Molecular Dynamics Investigation. PLoS ONE 9(1): e86365. doi:10.1371/journal.pone.0086365
Publication title
PLoS ONE
Document title
Human Lactate Dehydrogenase A Inhibitors: A Molecular Dynamics Investigation
Date
2014
Volume
9
Issue
1
Publisher DOI
10.1371/journal.pone.0086365
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
Member of collection
Attachment Size
1002.pdf 7.78 MB