CD38 is a nicotinamide adenine dinucleotide （NAD）-metabolizing enzyme responsible for catalyzing the synthesis of Ca^2＋ messengers. Its inhibitor plays an important role in probing the regulatory pathway and physiological function of CD38. For clearly understanding the effect of 2＇-substitution of nicotinamide mononucleotide （NMN） analogues on CD38 NADase inhibitory activity, a new kind of NMN analogues with two substituents at C-2＇ was investigated. Molecular dynamics （MD） simulation and quantum chemical calculation were used to investigate the mechanism by which 2＇-substitution affects the inhibitory activity. The results showed that two substituents at C-2＇ interfered the formation of covalent bond between C-1＇ of NMN analogues and CD38. The findings of this study will be helpful for comprehensively clarifying the structure-activity relationships of NMN- related CD38 NADase＇s inhibitor.
