Ligand-based and structure-based investigation for Alzheimer's disease from traditional chinese medicine.

Kai Hsin Liao,Mao-Feng Sun,Kuen-Bao Chen,Calvin Yu-Chian Chen,Wen-Yuan Lee,Cheng-Chun Lee

doi:10.1155/2014/364819

Abstract

Alzheimer's disease is a neurodegenerative disease that was conventionally thought to be related to the sedimentation of beta-amyloids, but drugs designed according to this hypothesis have generally failed. That FKBP52 can reduce the accumulation of tau proteins, and that Tacrolimus can reduce the pathological changes of tau proteins are new directions away from the long held amyloid-beta-centric concept. Therefore, the screening of traditional Chinese medicine compounds for those with higher affinity towards FKBP52 than Tacrolimus may be a new direction for treating Alzheimer's disease. This study utilizes ligand-based and structure-based methods as the foundation. By utilizing dock scores and the predicted pIC50 from SVM, MLR, and Bayesian Network, several TCM compounds were selected for further analysis of their protein-ligand interactions. Daphnetoxin has higher affinity and complex structure stability than Tacrolimus; Lythrancine II exhibits the most identical trends in FKBP52 interactions as Tacrolimus, and 20-O-(2′E,4′E-decadienoyl)ingenol may be further modified at its hydrocarbon chain to promote interaction with FKBP52. In addition, we observed the residue Tyr113 of FKBP52 may play a key role in protein-ligand interaction. Our results indicate that Daphnetoxin, 20-O-(2′E,4′E-decadienoyl)ingenol, and Lythrancine II may be starting points for further modification as a new type of non-amyloid-beta-centric drug for Alzheimer's disease.

Highlights

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease [1,2,3] with symptoms ranging from intellectual deterioration, cognitive impairment [4, 5] to abnormal behavior, personality changes, depression, and sleep disorders [6, 7]
FKBP52 was initially discovered as a cochaperone of steroid receptor heterocomplexes [19, 20] and is a member of the FK506binding protein (FKBP) of immunophilins
The ten representative descriptors determined by Genetic Function Approximation (GFA) were ES Count aaCH, ES Count sOH, ES Sum aaCH, ES Sum sssN, Num Rings6, Molecular PolarSurfaceArea, CHI 2, Jurs TPSA, Minimized Energy, and Shadow Ylength, suggesting certain relationships between electrotopological properties and polar surface area of ligands with bioactivity (Table S1)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease [1,2,3] with symptoms ranging from intellectual deterioration, cognitive impairment [4, 5] to abnormal behavior, personality changes, depression, and sleep disorders [6, 7]. Formation of β-amyloid plaques [10,11,12,13] and neurofibrillary tangles due to abnormal phosphorylation of tau proteins [14] have been linked to AD. Pioneer research has discovered that the concentration of FKBP52, a FK506-binding protein, is of high density in brain [15] and 40 times higher within the central nervous system than in the immune system [16]. FKBP52 is related to immune functions but is important for CNS protective properties. They can bind with highly phosphorylated tau proteins [16], thereby reducing the accumulation of tau proteins [16,17,18]. FKBP52, which possesses a chaperone function, has a PPIase domain called FK506-binding domain (FKBD), composed of the first 138 amino acids from the N-terminal, exhibits peptidylprolyl isomerase (PPIase) activity, and plays an important role in regulating tau proteins

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