Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Clark, David E.¹  Waszkowycz, Bohdan^1,4  Wong, Melanie¹  Lockey, Peter M.¹  Adalbert, Robert^3,5  Gilley, Jonathan^3,5  Clark, Jonathan²  Coleman, Michael P.^3,5 

[1] Charles River Labs, 8-9 Spire Green Ctr, Harlow CM19 5TR, Essex, England

[2] Babraham Biosci Technol Ltd, Babraham Res Campus, Cambridge CB22 3AT, England

[3] Babraham Inst, Babraham Res Campus, Cambridge CB22 3AT, England

[4] Univ Manchester, Canc Res UK Manchester Inst, Drug Discovery Unit, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[5] Univ Cambridge, Dept Clin Neurosci, John van Geest Ctr Brain Repair, Robinson Way, Cambridge CB2 0PY, England

关键词: NAMPT;    Virtual screening;    Axon degeneration;    Molecular docking;    Similarity searching;   

DOI  :  10.1016/j.bmcl.2016.04.039

来源: Elsevier

【 摘 要 】

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. (C) 2016 The Authors. Published by Elsevier Ltd.

【 授权许可】

Free