Identıfıcatıon Of Novel Nıcotınamıde Phosphorıbosyltransferase (Nampt) Inhıbıtıor Candıdates Vıa Vırtual Screenıng Campaıgn And Evaluatıon Of Theır Bıologıcal Actıvıtıes


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