Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.
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Peer-reviewed
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Abstract
NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.
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Keywords
Axon degeneration, Molecular docking, NAMPT, Similarity searching, Virtual screening, Animals, Antineoplastic Agents, Axons, Caco-2 Cells, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Cytochrome P-450 Enzyme System, Cytokines, Dose-Response Relationship, Drug, Drug Discovery, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Structure, Nicotinamide Phosphoribosyltransferase, Structure-Activity Relationship
Journal Title
Bioorg Med Chem Lett
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Journal ISSN
0960-894X
1464-3405
1464-3405
Volume Title
26
Publisher
Elsevier BV
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Sponsorship
Medical Research Council (MR/L003813/1)
Medical Research Council (MR/N004582/1)
Medical Research Council (MR/N004582/1)