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• A novel strategy was proposed for the comprehensive analysis of Magnolia officinalis. • A total of 103 compounds were identified from the whole plant of Magnolia officinalis. • Multidimensional chemical-biological analysis of Magnolia officinalis was established. • The 6 parts of Magnolia officinalis were explored and compared for the first time. • Magnolol and honokiol were found to be synergistic α-glucosidase inhibitors. Magnolia bark is a traditional Chinese medicine used for hypoglycaemia. With the widespread use of Magnolia bark, its resources are facing a serious shortage. To address this issue, a strategy based on high-coverage mass spectrometry (HCMS) and multidimensional chemical-biological analysis (MCBA) was proposed for the comprehensive exploration of Magnolia officinalis which is the main source of Magnolia bark. The strategy is divided into three main steps. In the first step, the stem bark, stem xylem, root bark, root xylem, leaf and rootlet of Magnolia officinalis were comprehensively analyzed using high-coverage mass spectrometry. In the second step, multivariate statistical analysis was used to explore the heterogeneity of the six parts and detect differential chemical components. In the third step, a combination of experimental screening and molecular docking was used to explore α-glucosidase inhibitors from Magnolia officinalis. Multidimensional chemical-biological analysis (MCBA) of Magnolia officinalis was achieved by combining the last two steps. Finally, a total of 103 compounds were identified from the whole plant of Magnolia officinalis. Differential components of stem bark, stem xylem, leaf, root bark, root xylem and rootlet were systematically revealed. A pair of positional isomers, namely magnolol and honokiol, were found to be α-glucosidase inhibitors. The activity of their combination is superior to that of each single compound, indicating that magnolol and honokiol are in a synergistic relationship. This strategy contributes to comprehensive exploitation of functional plants and effective alleviation of resource shortage. This study also provides a research paradigm for other similar traditional Chinese medicinal plants. [ABSTRACT FROM AUTHOR]

• A novel method of combinatorics-based chemical characterization was proposed. • A total of 131 compounds were characterized from Marsdenia tenacissima. • PCA and OPLS-DA were applied to compare different parts of Marsdenia tenacissima. • Tenacissoside H was discovered as a differential component between stems and roots. • The DPPH-scavenging activity and α-glucosidase inhibitory activity were compared. Marsdenia tenacissima is a traditional Chinese medicinal plant used for treating cancer, and its main medicinal part is the stem. Considering the resource shortage of M. tenacissima , it is of great significance to improve its utilization efficiency. Steroids and caffeoylquinic acids, the two main components of M. tenacissima , are composed of several basic structures. Based on this rule, a novel strategy of combinatorics-based chemical characterization was proposed to analyze the constituents of roots, stems and leaves of M. tenacissima. Combinatorics was used to generate a compound library for structure alignment, which has the advantages of wide coverage and high specificity. Steroids are composed of four basic parts: core skeleton (C), substituent at position 11 (A), substituent at position 12 (B) and sugar moiety (S). Based on combinatorics, a compound library consisting of 1080 steroids was generated. Diagnostic neutral loss has been used to effectively predict the substituents at position 11 and 12 of steroids, including acetyl, 2-methylpropionyl, tigloyl, 2-methylbutyryl and benzoyl. As a result, 131, 131 and 99 components were detected from the roots, stems and leaves of M. tenacissima , respectively. Principal component analysis (PCA) was used to analyze the differences of roots, stems and leaves, and orthogonal partial least squares-discriminant analysis (OPLS-DA) was further applied to find differential components. Tenacissoside H, a critical indicator component for quality evaluation of the stem, has been proved to be a differential component between roots and stems. Notably, the relative content of tenacissoside H in the roots was significantly higher than that in the stems. The bioactivity comparison showed that roots, stems and leaves of M. tenacissima had similar scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. However, their α-glucosidase inhibitory activity was ranked as leaves > stems > roots. Therefore, besides stems, the other parts of M. tenacissima have potential medicinal value. This study not only helps to develop the resource of M. tenacissima , but also provides a paradigm for the research of other similar medicinal plants. [ABSTRACT FROM AUTHOR]

• Proposal of a novel concept of lead chemome for drug discovery. • Development of a practical and efficient strategy to discover lead chemome. • Establishment of natural chromatogram-effect correlation (NCEC) based on traditional Chinese medicines. • Establishment of natural structure-effect correlation (NSEC) based on natural products. • Integration of NCEC and NSEC to screen active compounds for the first time. Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC 50 values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC 50 values. The structure–activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of "stem is the medicinal part of Mahonia bealei and Mahonia fortunei ". Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants. [ABSTRACT FROM AUTHOR]