Computational drug repurposing: Posaconazole emerges as a potent NAMPT inhibitor, offering promise for precision cancer therapeutics

Abstract

Cancer cells require high NAD+ levels to sustain their rapid growth, relying primarily on the salvage pathway for NAD+ replenishment. The overexpression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in this pathway, correlates with the increased NAD+ demand in cancer cells, making it a critical target for anticancer drug development. Moreover, a few small-molecule inhibitors targeting NAMPT have shown promise in restricting tumor growth, further establishing NAMPT as a potential therapeutic target in cancer treatment. This computational study aims to identify potential NAMPT inhibitors that can effectively suppress the over-activated NAD+ salvage pathway in cancer cells, thereby inhibiting tumor growth. Instead of developing novel inhibitors from scratches, this study specifically aims to screen approved drugs using computational methods to find a repurposable drug that binds strongly to NAMPT, offering a faster and cost-effective approach to cancer treatment. Initially, molecular docking was employed to screen 1,615 approved drugs, followed by a detailed examination of drug-protein interactions using advanced computational techniques, including molecular dynamics simulation, principal component analysis, and MM-PBSA. Among the screened compounds, posaconazole, an antifungal drug, emerged as a top candidate with a high affinity for the NAMPT active site, surpassing a known synthetic NAMPT inhibitor. Molecular dynamics simulations and MMPBSA confirmed the stability of the NAMPT-posaconazole complex, further supporting its potential as a NAMPT inhibitor. However, further in vitro, in vivo, and clinical validation is essential to confirm its anticancer efficacy.