Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Abstract

Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.

From Plant to Chemistry: Sources of Antinociceptive Non-Opioid Active Principles for Medicinal Chemistry and Drug Design

“…They demonstrated a significant reduction of thermal, but not mechanical hyperalgesia and discovered that the compound interacts with the serotonin system, inhibits MAO-A activity, and activates 5-HT7 receptors at the spinal but not at the supraspinal level. They also confirmed fisetin (60) antihyperalgesic action (15-45 mg/kg) on thermal hyperalgesia and mechanical allodynia in diabetic neuropathic pain model, by its antioxidant activity in dorsal root ganglia and spinal cord of mice, but not supraspinal GABAA receptor involvement.…”

“…hupehana (Craib) T.C.Chen, fisetin (3,3′,4′,7-tetrahydroxyflavone) (60, Figure 34), a flavonoid compound able to overcome the BBB, is one of the most studied for its analgesic, antidepressant, and neuroprotective action. It was deeply investigated fisetin (60) analgesic action in the CCI model (15 and 45 mg/kg administered p.o. twice a day for 3 weeks) [43].…”

“…Essential oil is rich in flavonoids and lignans, while the major chemical compound of the aerial part is betulinic acid (61, Figure 35), a pentacyclic triterpenoid with anti-bacterial, anti-cancer, anti-HIV, anti-diabetic, and anti-inflammatory activities, but also with protective action against Alzheimer's disease and atherosclerosis. It was deeply investigated fisetin (60) analgesic action in the CCI model (15 and 45 mg/kg administered p.o. twice a day for 3 weeks) [43].…”

“…Finally, it has recently been demonstrated that 5-CQA forms a stable interaction with glutamate AMPA receptor at the GluA1 subunit, mainly through Van der Waals and electrostatic interactions. 5-CQA binding leads to GluA1 expression inhibition, reducing the abnormal AMPA receptor activation in neuropathic pain [ 60 ].…”

Full title: Function, mechanism of action, metabolism, and commercial application of Lonicera japonica: a review

“…Many studies have indicated that Lonicera japonica extracts and functional components found in Lonicera japonica extracts, such as flavonoids, phenolic acids, and polysaccharides, could treat many conditions. They included inflammatory diseases [22] , vascular senescence [23] , diabetes, obesity [24] , hyperuricemia [25][26] , and pain [27][28] , atherosclerosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, hypertension [29] , Alzheimer's disease, cancer [30][31] , etc. Before discussing the health effects of Lonicera japonica against these diseases, the pathogenesis of the diseases should be reviewed, so that we can better understand how the functional components of Lonicera japonica play a role in preventing the occurrence and development of the diseases.…”