title: Targeting NAMPT for Therapeutic Intervention in Cancer and Inflammation: Structure-Based Drug Design and Biological Screening.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is a rate limiting enzyme that plays an important role in the synthesis of nicotinamide adenine dinucleotide (NAD) via a salvage pathway. Along with a role in bioenergetics, NAMPT regulates the activity of proteins such as SIRT-1 that utilize NAD as a cofactor. As NAD metabolism is usually high in diseased conditions, it has been hypothesized and proven that NAMPT is over expressed in various cancers and inflammatory disorders. Inhibitors targeting NAMPT could therefore be useful in treating disorders arising from aberrant NAMPT signalling. In this study, inhibitors against NAMPT were designed using an energy-based pharmacophore strategy and evaluated for efficacy in cellular assays. Besides reducing cellular pools of NAD and NMN, NAMPT inhibitors decreased concentrations of reactive oxygen species as well as mRNA levels of TNFα and IL6, thereby implicating their potential in alleviating the inflammatory process. In addition, reduced NAD levels corroborated with an induction of apoptosis in prostate cancer cell lines.
authors: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, AP, 500078, India.
authors: Venkat K
authors: VK
authors: Pulla
authors: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, AP, 500078, India.|Incozen Therapeutics Private Limited, 450, Alexandria Knowledge park, Phase-I, Shameerpet, Hyderabad, AP, 500078, India.
authors: Dinavahi S
authors: DS
authors: Sriram
authors: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, AP, 500078, India.
authors: Vijay
authors: V
authors: Soni
authors: Incozen Therapeutics Private Limited, 450, Alexandria Knowledge park, Phase-I, Shameerpet, Hyderabad, AP, 500078, India.
authors: Srikant
authors: S
authors: Viswanadha
authors: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, AP, 500078, India.
authors: Dharmarajan
authors: D
authors: Sriram
authors: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, AP, 500078, India.
authors: Perumal
authors: P
authors: Yogeeswari
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008958:Models, Molecular; D009243:NAD / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016207:Cytokines; D017382:Reactive Oxygen Species; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: NAMPT inhibitors; cancer; docking; e-pharmacophore; neuroinflammation; nicotinamide adenine dinucleotide; prostate cancer; reactive oxygen species