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(ADP-ribose) 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 μM) and GF8 (NAMPT IC50 = 7.31 ± 1.59 μM) 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 μM, respectively.

中文翻译：

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通过基于药效基团的虚拟筛选，将小分子尿素衍生物鉴定为新型NAMPT抑制剂。

烟酰胺磷酸核糖基转移酶（NAMPT）催化烟酰胺（NAM）与5-磷酸核糖基-1-原磷酸酯（PRPP）的缩合反应，以产生烟酰胺单核苷酸（NMN），这是哺乳动物酰胺烟酰胺腺嘌呤二核苷酸（NAD +）合成中的限速酶。最近，由于最近的发现，包括聚（ADP-核糖）聚合酶（PARP），单（ADP-核糖）转移酶（ART）和sirtuins（SIRT）在内的几种酶都使用NAD +作为底物，细胞内NAD +受到了广泛关注。 ，表明细胞内NAD +水平可能通过这些酶调节细胞因子的产生，代谢和衰老。NAMPT被发现在各种类型的癌症中均被上调，并且鉴于其在NAD +挽救途径中的重要性，NAMPT被认为是开发新的癌症疗法的有吸引力的目标。在这项研究中，已报道的带有酰胺，氰基胍和尿素支架的NAMPT抑制剂被用于生成药效基团模型，并针对ZINC数据库进行了基于药效基团的虚拟筛选研究。在过滤步骤之后，鉴定了十个命中并评估了它们在体外对NAMPT的抑制作用。化合物GF4（NAMPT IC50 = 2.15±0.22μM）和GF8（NAMPT IC50 = 7.31±1.59μM）被鉴定为NAMPT的新型尿素抑制剂，对人HepG2肝癌细胞系也显示出细胞毒活性，IC50值为15.20±分别为1.28和24.28±6.74μM。尿素支架用于生成药效团模型，并针对ZINC数据库进行了基于药效团的虚拟筛选研究。在过滤步骤之后，鉴定了十个命中并评估了它们在体外对NAMPT的抑制作用。化合物GF4（NAMPT IC50 = 2.15±0.22μM）和GF8（NAMPT IC50 = 7.31±1.59μM）被鉴定为NAMPT的新型尿素抑制剂，对人HepG2肝癌细胞系也显示出细胞毒活性，IC50值为15.20±分别为1.28和24.28±6.74μM。尿素支架用于生成药效团模型，并针对ZINC数据库进行了基于药效团的虚拟筛选研究。在过滤步骤之后，鉴定了十个命中并评估了它们在体外对NAMPT的抑制作用。化合物GF4（NAMPT IC50 = 2.15±0.22μM）和GF8（NAMPT IC50 = 7.31±1.59μM）被鉴定为NAMPT的新型尿素抑制剂，对人HepG2肝癌细胞系也显示出细胞毒活性，IC50值为15.20±分别为1.28和24.28±6.74μM。