Homology Modeling of Human Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase 2: Insights into Isoenzyme-Specific Differences Using Molecular Docking Simulatons

Background: Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that plays crucial roles in energy metabolism, DNA repair and cell death. Due to the high proliferation rate and the high energy necessity in cancer cells, NAD biosynthesis and salvage is required. Owing to the NAD importance in cancer cells, NAD salvage/recycling enzymes are targets for drug discovery. Methods: Herein we focused on NMNAT is a housekeeping enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. In mammals, three NMNAT isoforms, nuclear NMNAT1, cytoplasmic NMNAT2 and mitochondrial NMNAT3 have been identified. Results: As there is no crystal structure for hNMNAT2, 3D structure models were built based on hNMNAT1 (42% identity) and hNMNAT3 (41.5% identity). To date, only a few hNMNAT inhibitors have been reported so far in the literature: Gallotannin, some NAD analogues and aminophenylsulfonamide derivatives. With the aim of investigating the differences in isoenzyme structures and catalytic properties in molecular level, molecular docking studies of compounds 1-5 were performed. Conclusion: Finally, this study might be helpful for the development of inhibitors potentially useful as new chemotherapeutics targeting NMNATs.