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

Ozgencil F., EREN G., ÖZKAN Y., GÜNTEKİN ERGÜN S., ATALAY R.

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.28, sa.1, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 28 Sayı: 1
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.bmc.2019.115217
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, Chimica, EMBASE, MEDLINE
  • Anahtar Kelimeler: NAMPT, Pharmacophore modeling, Virtual screening, HepG2, NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE NAMPT, ADENINE-DINUCLEOTIDE BIOSYNTHESIS, POTENT INHIBITORS, CYP2C9 INHIBITION, DISCOVERY, CANCER, AMIDES, DATABASE, DESIGN, PHASE
  • Gazi Üniversitesi Adresli: Evet

Özet

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.