title: Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.
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.
authors.affiliation: Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom. Electronic address: david.clark@crl.com.
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.affiliation: Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.affiliation: Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lockey
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Adalbert
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.affiliation: Babraham Bioscience Technologies Ltd, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clark
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Axon degeneration; Molecular docking; NAMPT; Similarity searching; Virtual screening