Research Information System
Thesis Type: Postgraduate
Institution Of The Thesis: Gazi University, Sağlık Bilimleri Enstitüsü, FARMASÖTİK KİMYA ANABİLİM DALI, Turkey
Approval Date: 2019
Thesis Language: Turkish
Student: FİKRİYE ÖZGENCİL
Supervisor: Gökçen Eren
Abstract:
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of
nicotinamide 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(ADP-ribose) polymerase (PARP) and the Sirtuin family, 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. Several classes of potent
and selective small-molecule NAMPT inhibitors have been reported in the literature. In
this study, the reported NAMPT inhibitors bearing amide, urea and cyanoguanidine
scaffolds were used to generate pharmacophore models and virtual screening studies
against ZINC database were performed. After filtering step, ten hits were identified,
purchased and evaluated for their in vitro NAMPT inhibitory effects. Finally, compounds
GF4 (NAMPT IC50=2,26 μM) and GF8 (NAMPT IC50=7,42 μM ) were identified as new ureatyped
inhibitors of NAMPT.
Key Words : NAMPT, Virtual Screening, Pharmacophore Modeling