Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 402202, Taiwan.
Int J Mol Sci. 2022 Apr 5;23(7):4033. doi: 10.3390/ijms23074033.
JAK inhibition is a new strategy for treating autoimmune and inflammatory diseases. Previous studies have shown the immunoregulatory and anti-inflammatory effects of and 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.
JAK 抑制是治疗自身免疫和炎症性疾病的一种新策略。先前的研究表明，迷迭香酸（RosA）、丹酚酸 A（SalA）、丹酚酸 C（SalC）、虎杖苷、丹酚酸 B 和咖啡酸乙酯的免疫调节和抗炎作用，并提示其酚酸的生物活性涉及 JAK-STAT 途径，但尚不清楚这些作用是否通过 JAK 抑制发生。用 AutoDock Vina 将迷迭香酸（RosA）、丹酚酸 A（SalA）、丹酚酸 C（SalC）、虎杖苷、丹酚酸 B 和咖啡酸乙酯（CY）对接至 JAK（PDB：6DBN），得到的 JAK 结合亲和力分别为-8.8、-9.8、-10.7、-10.0、-10.3 和-9.7 kcal/mol。它们的预测构象使它们能够与 JAK 激酶结构域的铰链区域和 N 端和 C 端结构域形成氢键。结合亲和力最大的化合物 SalC 的苯并呋喃核心位于 Leu959 附近，如托法替尼的吡咯嘧啶。在保持这种关系的同时，设计了具有-12.2 kcal/mol 结合亲和力的 SalC 衍生物。对接结果表明，这些酚酸作为 JAK 抑制剂的后续研究可能是有意义的。此外，SalC、RosA、CY 和 SalA 的衍生物可以产生更好的结合亲和力或生物利用度评分，表明它们的结构可能适合作为设计新型 JAK 抑制剂的支架。
