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.

Chengyan Long,Sixing Huang,Li Zhang,Xiaomei Zhang,Yanlei Guo,Wei Du,Dajian Yang,Yang Yang,Yong Yang

doi:10.1155/2021/6676470

Abstract

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.

Highlights

Traditional Chinese medicine (TCM) and natural products represent a huge source of diverse new drugs due to their potent and highly varied physiological activities
The greatest structural difference of 55 sesquiterpene pyridine alkaloids from Tripterygium lied in 2-(carboxyalkyl) nicotinic acid part possessing pyridine ring and the pharmacophore model-5 (Pm-05) was the best model that consisted of three features including being hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobic (HY), especially hydrophobic group located in the pyridine ring. 2-(Carboxyalkyl) nicotinic acid part possessing a pyridine ring system as the pharmacologically active center and the core of structural diversity of alkaloids from Tripterygium wilfordii was proposed
Based on related literature and the HR-MSDatabase of macrocyclic dilactone skeleton alkaloids from Tripterygium established by our research group, data on sesquiterpene pyridine alkaloids from Tripterygium were extracted, and their molecular structures were converted into the standard Canonical SMILES format using PubChem database and ChemSpider database, for target prediction of compounds [19, 20]

Summary

Introduction

Traditional Chinese medicine (TCM) and natural products represent a huge source of diverse new drugs due to their potent and highly varied physiological activities. Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. F. (TWHF), a typical traditional Chinese medicine plant, have been widely used to treat autoimmune diseases and neurodegenerative diseases including rheumatoid arthritis, systemic lupus erythematosus, and Parkinson’s disease in China [1,2,3]. Chemical and pharmacological studies have demonstrated that alkaloids, diterpenes, triterpenes, and lignans were major bioactive components found in T. wilfordii responsible for the overall curative effects [4,5,6]. Triptolide and celastrol are considered as predominantly active natural products of TWHF and are used as a remedy for inflammatory and autoimmune diseases [7, 8]. Toxicity restricts the further development of triptolide and celastrol [10]

Methods

Results

Conclusion