Investigation of the effect of 2＇-substitution of NMN analogues on CD38 NADase inhibitory activity

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.

CD38是一种烟酰胺腺嘌呤二核苷酸(NAD)代谢酶,可以催化生成不同的钙信号信使。它的酶抑制剂对于CD38调控的信号通路和生理功能的进一步研究有重要作用。为了深入了解2'位取代基对烟酰胺单核苷酸(NMN)类似物抑制CD38酶活性的影响,本文研究了一种2'位有两个取代基的新NMN类似物,同时使用分子动力学模拟和量子化学计算方法探索2'位取代基影响活性的原因。结果表明2'位有两个取代基时,会干扰核苷酸C1'与CD38之间共价键的形成。本研究将有助于全面理清NMN类似物作为CD38酶抑制剂的构效关系。