Targeting the NAD+ salvage pathway: Identification of bifunctional NAMPT inhibitors and SIRT1 activators through pharmacophore-based virtual screening
Bioorganic and Medicinal Chemistry, cilt.141, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 141
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.bmc.2026.118754
- Dergi Adı: Bioorganic and Medicinal Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: Dual-acting, NAMPT, Pharmacophore, SIRT1, Virtual screening
- Gazi Üniversitesi Adresli: Evet
Özet
Nicotinamide phosphoribosyltransferase (NAMPT) and Sirtuin 1 (SIRT1) are key regulators of cellular metabolism and NAD+ homeostasis, representing attractive targets in cancer therapy. In this study, we identified novel bifunctional small molecules acting as simultaneous NAMPT inhibitors and SIRT1 activators through pharmacophore-based virtual screening, followed by biochemical validation with computational support. Among the candidates, compound F1 emerged as a leading hit, exhibiting potent NAMPT inhibition (IC50 = 0.89 μM) and selective SIRT1 activation (EC1.5 = 16.45 μM) in vitro. In cellular assays using the human Hep3B hepatocellular carcinoma cells, F1 reduced cell viability (IC50 = 17.03 μM) through a p53-independent mechanism. Notably, despite its NAMPT inhibitory activity in vitro, F1 treatment resulted in a time-dependent increase in intracellular nicotinamide adenine dinucleotide (NAD+) levels (∼1.5-fold) and an elevated NAD+/NADH ratio within 24 h, accompanied by upregulation of NAMPT and SIRT1 protein expression, reflecting a compensatory response aimed at maintaining NAD+ homeostasis. This elevated NAD+ level, coupled with SIRT1 activation, led to a marked reduction in global lysine acetylation. Collectively, our findings demonstrate that F1 disrupted cancer cell homeostasis by inducing a unique metabolic reprogramming of the NAD+ salvage pathway, positioning it as a promising scaffold for multi-target metabolic modulation.