The mitochondrial bioenergetics hypothesis postulates a critical role of mitochondrial activity in aging, which leads to the development of age-related diseases if disturbed. NAD+ and NADH generate a powerful oxidoreductive system driving ATP production in mitochondria, therefore, the maintenance of the NAD+/NADH ratio is crucial for the metabolic homeostasis in cells. The activation of nicotinamide phosphoribosyl transferase (NAMPT) is a superior approach to increase cellular levels of NAD+ since it is a rate-limiting enzyme of NAD+ salvage pathway producing NAD+ precursor nicotinamide mononucleotide. NAMPT inhibitors are, however, also desired by pharmaceutical applications due to their potency in limiting the growth of cancer cells. The present work demonstrates an in-silico approach for screening NAMPT activity modulators using compound libraries from traditional African, Chinese, and Russian medicinal plants. The compounds predicted to pass the blood-brain barrier, with low predicted toxicity and desirable pharmacokinetic and drug-likeness characteristics, were subjected to further selection by molecular docking using CB-Dock2. A panel of 21 compounds, including known NAMPT activators, inhibitors, negative controls, and randomly chosen compounds, was used to validate the docking method. The selection yielded 17 compounds with increased docking scores when tested against 6 co-crystallized structures of NAMPT. Their 2D protein-ligand interactions were critically evaluated and correlated with known interactions of the NAMPT activators and inhibitors with the active and allosteric sites of the enzyme. The selected compounds are suitable for the experimental pharmaceutical developments of drugs for aging, neurological diseases, and cancer treatments.
