Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening

Date

2020-01-01

Author

Ozgencil, Fikriye
EREN, GÖKÇEN
ÖZKAN, YEŞİM
GÜNTEKİN ERGÜN, SEZEN
Atalay, Rengül

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Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-prophosphate (PRPP) to yield nicotinamide mononucleotide (NMN), a rate limiting enzyme in a mammalian salvage pathway of nicotinamide adenine dinucleotide (NAD(+)) synthesis. Recently, intracellular NAD(+) has received substantial attention due to the recent discovery that several enzymes including poly(ADPribose) polymerases (PARPs), mono(ADP-ribose) transferases (ARTs), and sirtuins (SIRTs), use NAD(+) as a substrate, suggesting that intracellular NAD(+) level may regulate cytokine production, metabolism, and aging through these enzymes. NAMPT is found to be upregulated in various types of cancer, and given its importance in the NAD(+) salvage pathway, NAMPT is considered as an attractive target for the development of new cancer therapies. In this study, the reported NAMPT inhibitors bearing amide, cyanoguanidine, and urea scaffolds were used to generate pharmacophore models and pharmacophore-based virtual screening studies were performed against ZINC database. Following the filtering steps, ten hits were identified and evaluated for their in vitro NAMPT inhibitory effects. Compounds GF4 (NAMPT IC50 = 2.15 +/- 0.22 mu M) and GF8 (NAMPT IC50 = 7.31 +/- 1.59 mu M) were identified as new urea-typed inhibitors of NAMPT which also displayed cytotoxic activities against human HepG2 hepatocellular carcinoma cell line with IC50 values of 15.20 +/- 1.28 and 24.28 +/- 6.74 mu M, respectively.

Subject Keywords

Organic Chemistry, Clinical Biochemistry, Molecular Medicine, Biochemistry, Molecular Biology, Drug Discovery, Pharmaceutical Science

URI

https://hdl.handle.net/11511/62985

Journal

BIOORGANIC & MEDICINAL CHEMISTRY

DOI

https://doi.org/10.1016/j.bmc.2019.115217

Collections

Graduate School of Informatics, Article

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Citation Formats

F. Ozgencil, G. EREN, Y. ÖZKAN, S. GÜNTEKİN ERGÜN, and R. Atalay, “Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening,” BIOORGANIC & MEDICINAL CHEMISTRY, pp. 0–0, 2020, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/62985.