Abstract
BackgroundPre-B-cell colony enhancing factor 1 gene (PBEF1) encodes nicotinamide phosphoribosyltransferase (NMPRTase), which catalyses the rate limiting step in the salvage pathway of NAD+ metabolism in mammalian cells. PBEF1 transcript and protein levels have been shown to be elevated in glioblastoma and a chemical inhibitor of NMPRTase has been shown to specifically inhibit cancer cells.MethodsVirtual screening using docking was used to screen a library of more than 13,000 chemical compounds. A shortlisted set of compounds were tested for their inhibition activity in vitro by an NMPRTase enzyme assay. Further, the ability of the compounds to inhibit glioma cell proliferation was carried out.ResultsVirtual screening resulted in short listing of 34 possible ligands, of which six were tested experimentally, using the NMPRTase enzyme inhibition assay and further with the glioma cell viability assays. Of these, two compounds were found to be significantly efficacious in inhibiting the conversion of nicotinamide to NAD+, and out of which, one compound, 3-amino-2-benzyl-7-nitro-4-(2-quinolyl-)-1,2-dihydroisoquinolin-1-one, was found to inhibit the growth of a PBEF1 over expressing glioma derived cell line U87 as well.ConclusionsThus, a novel inhibitor has been identified through a structure based drug discovery approach and is further supported by experimental evidence.
Highlights
Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes nicotinamide phosphoribosyltransferase (NMPRTase), which catalyses the rate limiting step in the salvage pathway of NAD+ metabolism in mammalian cells
We report virtual screening of a large library of compounds and short listing of six candidate molecules that are likely to bind to NMPRTase
Docking The co-ordinates of the human NMPRTase (2GVGcomplex with the reaction product nicotinamide mononucleotide; 2GVJ- complex with an inhibitor, n-[4-(1benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylpropanamideFK866 were obtained from Protein Data Bank (PDB) [14]
Summary
Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes nicotinamide phosphoribosyltransferase (NMPRTase), which catalyses the rate limiting step in the salvage pathway of NAD+ metabolism in mammalian cells. PBEF1 transcript and protein levels have been shown to be elevated in glioblastoma and a chemical inhibitor of NMPRTase has been shown to inhibit cancer cells. Several molecular and biochemical abnormalities such as specific chromosomal aberrations, upregulation of epidermal growth factor receptor (EGFR), loss of phosphate and tensin homology (PTEN), have been clearly associated with gliomas. Some pathways associated with higher grade gliomas are upregulation of PDGFRA (platelet derived growth factor receptor a), CDK4 (cyclin dependent kinase 4) and down-regulation of retinoblastoma (RB1) [1]. NAD+, in and presents a possible strategy to counter the disease, through the inhibition of key enzymes in the pathway
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