Salvianolic acids from antithrombotic Traditional Chinese Medicine Danshen are antagonists of human P2Y1 and P2Y12 receptors

Abstract

Many hemorheologic Traditional Chinese Medicines (TCMs) that are widely-used clinically lack molecular mechanisms of action. We hypothesized that some of the active components of hemorheologic TCMs may function through targeting prothrombotic P2Y1 and/or P2Y12 receptors. The interactions between 253 antithrombotic compounds from TCM and these two G protein-coupled P2Y receptors were evaluated using virtual screening. Eleven highly ranked hits were further tested in radioligand binding and functional assays. Among these compounds, salvianolic acid A and C antagonized the activity of both P2Y1 and P2Y12 receptors in the low µM range, while salvianolic acid B antagonized the P2Y12 receptor. These three salvianolic acids are the major active components of the broadly-used hemorheologic TCM Danshen (Salvia militorrhiza), the antithrombotic molecular mechanisms of which were largely unknown. Thus, the combination of virtual screening and experimental validation identified potential mechanisms of action of multicomponent drugs that are already employed clinically.

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…The reversible and very potent antagonist ACT‐246475 (Caroff et al, 2015) is being tested in clinical trials for use in the prevention or treatment of cardiovascular events (Baldoni et al, 2014). In addition, a variety of moderately potent P2Y 12 receptor antagonists have been described, among them 4‐benzhydrylmorpholines (Ahn et al, 2016), flavonolignans (Bijak, Szelenberger, Dziedzic, & Saluk‐Bijak, 2018), and salvianolic acids (Liu et al, 2018). [ 3 H]PSB‐0413 is an antagonist radioligand, the tritiated form of AR‐C67085 ( 28 ), which binds to P2Y 12 receptors with a K D value of 4.6 nM (Ohlmann et al, 2013).…”

Salvianolic acid a inhibits platelet activation and aggregation in patients with type 2 diabetes mellitus

“…Recent researches on the action mechanisms of SAA have found that SAA can antagonize the activity of both [27]. Moreover, pretreatment with SAA on platelets caused an increase in the cAMP level in platelets activated by ADP, which indicates that SAA might possess antithrombotic activities [28].…”

Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources

“…They focused on compounds from three herbs: cimicifugae (Cimicifuga foetida L.), ganoderma (Ganoderma lucidum Karst), and licorice (Glycyrrhiza uralensis Fisch), as some studies have suggested that they demonstrate antithrombosis activity (Yi et al, 2017). Liu et al (2018) performed a similar screening campaign to find novel ligands for P2Y1 and P2Y12 receptors that could be used as antithrombotic drugs. They evaluated 253 compounds from Traditional Chinese Medicines and tested 11 hits through in vitro assays, including salvianolic acids from Salvia militorrhiza (Liu et al, 2018).…”

“…Liu et al (2018) performed a similar screening campaign to find novel ligands for P2Y1 and P2Y12 receptors that could be used as antithrombotic drugs. They evaluated 253 compounds from Traditional Chinese Medicines and tested 11 hits through in vitro assays, including salvianolic acids from Salvia militorrhiza (Liu et al, 2018). Table 2 demonstrates some studies that applied virtual screening, using the molecular docking strategy to discover novel ligands for P2 receptors.…”

“…In the field of drug discovery and development, MD has been used extensively for the refinement and optimization of constructed P2 receptor homology models to build templates for molecular docking assays (Zylberg et al, 2007;Trujillo et al, 2015;Junker et al, 2016;Liu et al, 2018). MD simulations have also been used in the evaluation of structure-function relationships between the binding pocket of the P2 receptor of interest and the candidate hits obtained through docking assays (Zhou et al, 2017).…”