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. 2022 Apr 5;23(7):4033.
doi: 10.3390/ijms23074033.

The Potential Role of Phenolic Acids from Salvia miltiorrhiza and Cynara scolymus and Their Derivatives as JAK Inhibitors: An In Silico Study

Affiliations

The Potential Role of Phenolic Acids from Salvia miltiorrhiza and Cynara scolymus and Their Derivatives as JAK Inhibitors: An In Silico Study

Hui-Jun Liao et al. Int J Mol Sci. .

Abstract

JAK inhibition is a new strategy for treating autoimmune and inflammatory diseases. Previous studies have shown the immunoregulatory and anti-inflammatory effects of Salvia miltiorrhiza and Cynara scolymus and suggest that the bioactivity of their phenolic acids involves the JAK-STAT pathway, but it is unclear whether these effects occur through JAK inhibition. The JAK binding affinities obtained by docking Rosmarinic acid (RosA), Salvianolic acid A (SalA), Salvianolic acid C (SalC), Lithospermic acid, Salvianolic acid B and Cynarin (CY) to JAK (PDB: 6DBN) with AutoDock Vina are -8.8, -9.8, -10.7, -10.0, -10.3 and -9.7 kcal/mol, respectively. Their predicted configurations enable hydrogen bonding with the hinge region and N- and C-terminal lobes of the JAK kinase domain. The benzofuran core of SalC, the compound with the greatest binding affinity, sits near Leu959, such as Tofacitinib's pyrrolopyrimidine. A SalC derivative with a binding affinity of -12.2 kcal/mol was designed while maintaining this relationship. The docking results show follow-up studies of these phenolic acids as JAK inhibitors may be indicated. Furthermore, derivatives of SalC, RosA, CY and SalA can yield better binding affinity or bioavailability scores, indicating that their structures may be suitable as scaffolds for the design of new JAK inhibitors.

Keywords: AutoDock Vina; Cynara scolymus; Cynarin; Danshen; JAK; Janus kinase; Salvia miltiorrhiza; Salvianolic acid; artichoke; benzofuran.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A series of JAK inhibitors.
Figure 2
Figure 2
JAK inhibitor (ligand) and JAK complex. (a) Tofacitinib/PDB:3EYG(JAK1/2); (b) PF–06700841/PDB:6DBN(JAK1); (c) 3C9/PDB:4QT1(JAK3). Hydrogen bonds were shown as red lines.
Figure 3
Figure 3
The six phenolic acids in Salvia miltiorrhiza and Cynara scolymus. (a) Rosmarinic acid (RosA); (b) Cynarin (CY); (c) Salvianolic acid A (SalA); (d) Salvianolic acid C (SalC); (e) Lithospermic acid (LSA); and (f) Salvianolic acid B (SalB).
Figure 4
Figure 4
The lowest-energy configurations of six phenolic acids docked to JAKs: (af) docking to PDB: 6DBN, (gi) docking to PDB: 3EYG. Hydrogen bonds were shown as red lines.
Figure 4
Figure 4
The lowest-energy configurations of six phenolic acids docked to JAKs: (af) docking to PDB: 6DBN, (gi) docking to PDB: 3EYG. Hydrogen bonds were shown as red lines.
Figure 5
Figure 5
The characteristics of SalC in docking with JAK(PDB:6DBN) were found by comparing SalCt01~SalCt06. (a) SalC with encoding. The benzofurans of the compounds (bk) showed different positions from SalC in the docking. (l) is the ring-opened form of (k). The location of SalC’s benzofuran brings benefits to its binding affinity. Hydrogen bonds were shown as red lines with labels.
Figure 6
Figure 6
(ah) SalCm01~SalCm08 were designed with reference to the structure of SalC in order to obtain better ADME parameters or binding affinity to JAK than SalC. Hydrogen bonds were shown as red lines with amino acid residue labels.
Figure 7
Figure 7
(ah) Benzofuran derivatives with biological activity and JAK inhibition potential obtained by searching for “SalC” with SwissSimilarity. Hydrogen bonds were shown as red lines with amino acid residue labels.
Figure 8
Figure 8
Structures of RosA derivatives. Chlorogenic acid (CCA) is for reference and comparison.
Figure 9
Figure 9
Chemical structures of Cynarin and SalA derivatives.

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