A strategy to discover lead chemome from traditional Chinese medicines based on natural chromatogram-effect correlation (NCEC) and natural structure-effect correlation (NSEC): Mahonia bealei and Mahonia fortunei as a case study.

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 IC50 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 IC50 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.

A strategy to discover selective α-glucosidase/acetylcholinesterase inhibitors from five function-similar citrus herbs through LC-Q-TOF-MS, bioassay and virtual screening.

The lack of direct connection between traditional herbal medicines and multiple biological targets is a bottleneck in herbal research and quality evaluation. To solve this problem, a strategy for the discovery of active ingredients from function-similar herbal medicines based on multiple biological targets was proposed in this article. The technical route includes chromatographic separation, mass spectrometry analysis, enzymatic activity detection, pharmacophore analysis and molecular docking. Five citrus herbs of Citri Reticulatae Pericarpium (CRP), Citri Exocarpium Rubrum (CER), Citri Grandis Exocarpium (CGE), Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) were used as the research objects. A total of 136 chemical components were identified from above five herbs based on LC-Q-TOF-MS/MS and database matching. The extracts of the five herbs showed obvious inhibitory effects on α-glucosidase and acetylcholinesterase in a concentration-dependent manner. Interestingly, the different types of components in the herbs exhibited selectivity for different targets: flavanone glycosides are effective on α-glucosidase but ineffective on acetylcholinesterase; polymethoxyflavonoids are effective on acetylcholinesterase but ineffective on α-glucosidase. Furthermore, we found for the first time that the components in citrus herbs exhibit opposite structure-activity relationships on the above two targets. For example, the methoxy group can enhance the activity of compounds on acetylcholinesterase but weaken the activity of compounds on α-glucosidase. The selective action is a supplement to the "multi-components, multi-targets" system of herbal medicines. Pharmacophore analysis and molecular docking were applied to explore the interaction between active ingredients and biological targets from the perspective of ligands and receptors, respectively. By combining the above multiple technologies, a strong connection among herbal medicines, chemical components and multiple biological targets was established. This work not only helps to understand the similar function of citrus herbs for the treatment of diabetes and Alzheimer's disease, but also provides selective lead compounds for the development of related drugs. This strategy is also helpful to improve the quality evaluation of citrus herbs from the perspective of biological activity.