CD38 is a multifunctional enzyme/receptor expressed in a variety of mammalian tissues,regulating a wide range of physiological functions.Beginning with the previously reported compound 1,an inhibitor of human CD38 NAD...CD38 is a multifunctional enzyme/receptor expressed in a variety of mammalian tissues,regulating a wide range of physiological functions.Beginning with the previously reported compound 1,an inhibitor of human CD38 NADase,we synthesized a series of indole-based NH-substituted derivatives with modifications on alkyl chains,changes in substituent groups on aromatic rings,and differences in carbon chain lengths.Compounds 10,13,16 and 34 exhibited moderate inhibition of human CD38 NADase.Analysis of the structure-activity relationships showed that the phenylpropionyl moiety was very important for the inhibitory activity.This study provides information for the rational design of CD38 inhibitors.展开更多
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 physio...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.展开更多
基金by the National Natural Science Foundation of China(Nos.81172917,21272017).
文摘CD38 is a multifunctional enzyme/receptor expressed in a variety of mammalian tissues,regulating a wide range of physiological functions.Beginning with the previously reported compound 1,an inhibitor of human CD38 NADase,we synthesized a series of indole-based NH-substituted derivatives with modifications on alkyl chains,changes in substituent groups on aromatic rings,and differences in carbon chain lengths.Compounds 10,13,16 and 34 exhibited moderate inhibition of human CD38 NADase.Analysis of the structure-activity relationships showed that the phenylpropionyl moiety was very important for the inhibitory activity.This study provides information for the rational design of CD38 inhibitors.
基金National Natural Sciences Foundation of China(Grant No.91213302,81172917 and 31301156)
文摘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.
