The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.

α-Glucosidase (AG) has always been an indispensable drug target for the treatment of type 2 diabetes. Herein, an integrated method consisting of enzyme kinetics, multi-spectroscopy assay and molecular simulations was used to investigate the structure–activity relationship and interaction mechanism of flavonoids and AG. As a result, a small amount of flavonoids was found to present excellent inhibitory activity on AG, such as 3, 5, 6, 8, 10, 17, 19, 21, 22 and 34. Further analysis of the structure–activity relationship illustrated that hydroxylation at the positions C3, C6, C3′ and C4′ of flavonoids caused an increase in the inhibitory activity of AG, whereas the methoxylation at the corresponding positions would decrease the activity. Also, it was found that the glycosylation and hydrogenation of the C2C3 double bond would distinctly reduce the inhibition potency. Therefore, various groups at different positions of flavonoids exhibited an upward and downward tendency in the activity. According to the fluorescence quenching assay, all of the test flavonoids could effectively quench the intrinsic fluorescence of AG based on either the static or mixed static–dynamic mechanism. Besides, the thermodynamic parameters of the representative flavonoid 19 revealed the spontaneous characteristic of the binding process with AG, and highlighted the critical role of the hydrophobic interaction and hydrogen bonds. Moreover, the results obtained from the synchronous fluorescence, ANS-binding fluorescence, Fourier transform infrared and circular dichroism spectra illustrated that these active flavonoids could bind to the active site of AG and induce the rearrangement and conformation change of its secondary structures, which resulted in a significant inhibitory activity. Additionally, molecular modelling visualized the preferred binding conformation of flavonoids on AG, and further confirmed the great importance of the hydrophobic interaction and hydrogen bonds in the interaction. Such findings provided new insights for understanding the proposed interaction behavior between flavonoids and AG, and were helpful to develop novel AG inhibitors relying on the flavonoid scaffold for the treatment of type 2 diabetes.

Lamiophlomis rotata (Benth.) Kudo (LR) is an extensively used Chinese herbal medicine. It contains a variety of chemical constituents with significant biological activities that were first recorded in the classical masterpiece of Tibetan Medicine, Somaratsa. In this review, we summarize the information regarding the traditional uses, chemical constituents, pharmacological effects, clinical applications, quality control, toxicology, and pharmacokinetics of LR. At least 223 chemical constituents have been isolated from LR, including phenylethanoid glycosides, flavonoids, iridoids, volatile oils, et al. Their various physiological activities have been demonstrated as analgesic, hemostatic, anti-inflammatory, anti-tumor, marrow-supplementing, anti-bacterial, and immunity-strengthening. The clinical applications of LR and quality control are also discussed, as well as some existing problems. This article aims to provide more comprehensive information on the chemical composition, pharmacological activity, and clinical application of LR, so as to provide a theoretical basis for the further reasonable development of LR in clinical practice and of new drugs.