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

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.

Potential Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports

“…Among the new and most promising availability strategies, special attention has been given to bioactive molecules largely found in nature, namely, polyphenols, since their chemical structure with catechol methoxy and pyrogallol groups confer them notable health benefits, like antioxidant, anti-inflammatory, anti-bacterial, and antiproliferative activities, as well as the capacity to prevent neurological and cardiovascular pathologies, promote gastrointestinal health and vision without, it is believed, side-effects, and enhance wound healing [14][15][16][17][18][19][20][21][22][23]. In addition, polyphenols are also easier to obtain, water-soluble, and more economical than chemical drugs, and have already shown effectiveness in inhibiting JAK proteins and JAK/STAT signaling pathways [24][25][26][27][28]. Particularly, curcumin displayed the capability to relieve rheumatoid arthritis progression by suppressing inflammatory responses, synovial hyperplasia, and protein expression levels of phosphorylated JAK2 and STAT3 in mice with the collagen-induced arthritis model that were treated at a dose of 100 µM curcumin/day for almost three months [29], while in docking studies, salvianolic acid C exhibited a great binding affinity for JAK (10.7 kcal/mol) [24].…”

“…In addition, polyphenols are also easier to obtain, water-soluble, and more economical than chemical drugs, and have already shown effectiveness in inhibiting JAK proteins and JAK/STAT signaling pathways [24][25][26][27][28]. Particularly, curcumin displayed the capability to relieve rheumatoid arthritis progression by suppressing inflammatory responses, synovial hyperplasia, and protein expression levels of phosphorylated JAK2 and STAT3 in mice with the collagen-induced arthritis model that were treated at a dose of 100 µM curcumin/day for almost three months [29], while in docking studies, salvianolic acid C exhibited a great binding affinity for JAK (10.7 kcal/mol) [24]. In addition, phenolic-rich extracts of sweet cherries have already displayed a notable ability to scavenge cellular nitric oxide species and diminish inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression [30], while tea polyphenols showed the capacity to enhance the expression of growth factor VEGF-A, which, in turn, promotes vascular endothelial cell division, induces angiogenesis, and improves wound morphology, restoring the type III/I collagen ratio during wound healing in mice model [23].…”

Quantum Chemical Computations, Molecular Docking, and ADMET Predictions of Cynarin

“…Many studies have been conducted by researchers for cynarin, which has a wide range of biological activities: Some of these include janus kinase (JAK) inhibition [13], matrix metalloproteinase-9 (MMP-9) inhibition [14], spike (S) glycoprotein inhibition [15], inhibition on human colon cancer HT-29 and RKO. Cells [16], effects on inflammatory response in EA.hy926 human endothelial cells [17], and effects on amelanotic melanoma C32 and renal adenocarcinoma ACHN [18] have been reported.…”

The Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports

“…Among the new and most promising availability strategies, special attention has been given to bioactive molecules largely found in nature, namely polyphenolics, since their chemical structure with catechol methoxy and pyrogallol groups, confers them notable health benefits, like antioxidant, anti-inflammatory and antiproliferative activities, as well as capacity to prevent neurological and cardiovascular pathologies, without, it is believed, side-effects [14][15][16][17][18][19][20][21]. In addition, polyphenolics are also easier to obtain, water-soluble and more economical than chemical drugs, and have already shown effectiveness in inhibiting JAK proteins and JAK/STAT signalling pathways [22][23][24][25][26]. Particularly, curcumin displayed capability to relieve the rheumatoid arthritis progression by suppressing the inflammatory responses, synovial hyperplasia and protein expression levels of phosphorylated JAK2 and STAT3 in mice with collagen-induced arthritis model that were treated at a dose of 100 µM curcumin/day for almost three months [27], while, by docking studies, salvianolic acid C exhibited a great affinity binding for JAK (10.7 kcal/mol) [22].…”

“…In addition, polyphenolics are also easier to obtain, water-soluble and more economical than chemical drugs, and have already shown effectiveness in inhibiting JAK proteins and JAK/STAT signalling pathways [22][23][24][25][26]. Particularly, curcumin displayed capability to relieve the rheumatoid arthritis progression by suppressing the inflammatory responses, synovial hyperplasia and protein expression levels of phosphorylated JAK2 and STAT3 in mice with collagen-induced arthritis model that were treated at a dose of 100 µM curcumin/day for almost three months [27], while, by docking studies, salvianolic acid C exhibited a great affinity binding for JAK (10.7 kcal/mol) [22]. In addition, phenolic-rich extracts of sweet cherries have already displayed a notable ability to scavenge cellular nitric oxide species and diminish inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression [28].…”