Candidate NAMPT modulators from traditional African, Chinese, and Russian medicinal plants

Abstract

The mitochondrial bioenergetics hypothesis postulates a critical role of mitochondrial function in aging and its deterioration is a cause of multiple age-related diseases. A superior approach to counteract age-dependent decline in cellular NAD+ levels is to activate nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the NAD+ salvage pathway, thereby producing the NAD+ precursor, nicotinamide mononucleotide. NAMPT inhibitors are also desired due to their potency in limiting cancer cell growth. Here is presented an in-silico screening of NAMPT modulators using compounds from traditional African, Chinese, and Russian medicinal plants and by repurposing FDA libraries. The compounds were selected by prediction to pass the blood-brain barrier, for low toxicity, and desirable pharmacokinetic and drug-likeness characteristics, and by molecular docking with crystal structures of NAMPT. A panel of 21 compounds of known NAMPT activators, inhibitors, negative controls, and randomly chosen compounds was used to validate the docking method. 2D protein-ligand interactions of the candidate compounds were critically evaluated and compared with interactions of the control panel. The virtual screening selection yielded 17 compounds with decreased predicted {Delta}G when bound to 6 co-crystallized structures of NAMPT. The candidates were then sorted into three binding groups based on 2D interactions with NAMPT active and allosteric sites. The stability of NAMPT complexes with stylopine, hedychilactone A, and isobavachromene, as representatives of the three binding groups, was also confirmed by molecular dynamics simulations. The results of the virtual screening should be used for experimental development of anti-aging treatments and medicines for neurodegenerative diseases and brain cancer.