The Exploration of Novel Pharmacophore Characteristics and Multidirectional Elucidation of Structure-Activity Relationship and Mechanism of Sesquiterpene Pyridine Alkaloids from Tripterygium Based on Computational Approaches.

Sesquiterpene pyridine alkaloids are a large group of highly oxygenated sesquiterpenoids, which are characterized by a macrocyclic dilactone skeleton containing 2-(carboxyalkyl) nicotinic acid and dihydro-β-agarofuran sesquiterpenoid, and are believed to be the active and less toxic components of Tripterygium. In this study, 55 sesquiterpene pyridine alkaloids from Tripterygium were subjected to identification of pharmacophore characteristics and potential targets analysis. Our results revealed that the greatest structural difference of these compounds was in the pyridine ring and the pharmacophore model-5 (Pm-05) was the best model that consisted of three features including hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobic (HY), especially hydrophobic group located in the pyridine ring. It was proposed that 2-(carboxyalkyl) nicotinic acid part possessing a pyridine ring system was not only a pharmacologically active center but also a core of structural diversity of alkaloids from Tripterygium wilfordii. Furthermore, sesquiterpene pyridine alkaloids from Tripterygium were predicted to target multiple proteins and pathways and possibly played essential roles in the cure of Alzheimer's disease, breast cancer, Chagas disease, and nonalcoholic fatty liver disease (NAFLD). They also had other pharmacological effects, depending on the binding interactions between pyridine rings of these compounds and active cavities of the target genes platelet-activating factor receptor (PTAFR), cannabinoid receptor 1 (CNR1), cannabinoid receptor 1 (CNR2), squalene synthase (FDFT1), and heat shock protein HSP 90-alpha (HSP90AA1). Taken together, the results of this present study indicated that sesquiterpene pyridine alkaloids from Tripterygium are promising candidates that exhibit potential for development as medicine sources and need to be promoted.