Objective The mangrove tree Xylocarpus granatum J.Koenig(X.granatum)is a medicinal plant used to treat various diseases in several Asian countries.Many bioactive natural products have been isolated from the plants,par...Objective The mangrove tree Xylocarpus granatum J.Koenig(X.granatum)is a medicinal plant used to treat various diseases in several Asian countries.Many bioactive natural products have been isolated from the plants,particularly several groups of limonoids,including 18 xylogranatins(Xyl-A to R),all of which bear a furyl-δ-lactone core commonly found in limonoids.Based on a structural analogy with the limonoids obacunone and gedunin,we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β(GSK-3β),a major target for the treatment of neurodegenerative pathologies,viral infections,and cancers.Methods We investigated the binding of the 18 xylogranatins to GSK-3βusing molecular docking in comparison with two known reference GSK-3βATP-competitive inhibitors,LY2090314 and AR-A014418.For each compound bound to GSK-3β,the empirical energy of interaction(ΔE)was calculated and compared to that obtained with known GSK-3βinhibitors and limonoid triterpenes that target this enzyme.Results Five compounds were identified as potential GSK-3βbinders,Xyl-A,-C,-J,-N,and-O,for which the calculated empiricalΔE was equivalent to that calculated using the best reference molecule AR-A014418.The best ligand is Xyl-C,which is known to have marked anticancer properties.Binding of Xyl-C to the ATP-binding pocket of GSK-3βpositions the furyl-δ-lactone unit deep into the binding-site cavity.Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3βbinding.Structure-binding relationships are discussed.Conclusion GSK-3βmay contribute to the anticancer effects of X.granatum extract.This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3βmodulators.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
文摘Objective The mangrove tree Xylocarpus granatum J.Koenig(X.granatum)is a medicinal plant used to treat various diseases in several Asian countries.Many bioactive natural products have been isolated from the plants,particularly several groups of limonoids,including 18 xylogranatins(Xyl-A to R),all of which bear a furyl-δ-lactone core commonly found in limonoids.Based on a structural analogy with the limonoids obacunone and gedunin,we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β(GSK-3β),a major target for the treatment of neurodegenerative pathologies,viral infections,and cancers.Methods We investigated the binding of the 18 xylogranatins to GSK-3βusing molecular docking in comparison with two known reference GSK-3βATP-competitive inhibitors,LY2090314 and AR-A014418.For each compound bound to GSK-3β,the empirical energy of interaction(ΔE)was calculated and compared to that obtained with known GSK-3βinhibitors and limonoid triterpenes that target this enzyme.Results Five compounds were identified as potential GSK-3βbinders,Xyl-A,-C,-J,-N,and-O,for which the calculated empiricalΔE was equivalent to that calculated using the best reference molecule AR-A014418.The best ligand is Xyl-C,which is known to have marked anticancer properties.Binding of Xyl-C to the ATP-binding pocket of GSK-3βpositions the furyl-δ-lactone unit deep into the binding-site cavity.Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3βbinding.Structure-binding relationships are discussed.Conclusion GSK-3βmay contribute to the anticancer effects of X.granatum extract.This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3βmodulators.
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.
