Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1_Journal of Biomedical Engineering

Authors：

LIN Lin ^1,2,3 , CHANG Jingjie ¹ , TIAN Yaozhou ^1,2 ,  CHEN Jiao ^1,2

1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, P. R. China;
2. Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P. R. China;
3. Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P. R. China;

Corresponding author：

CHEN Jiao, Email: chenjiao@njucm.edu.cn

Keywords：

Compound Kushen injection; p21-Activated kinase 1; 14α-Hydroxymatrine; Pancreatic cancer; Molecular docking; Molecular dynamics simulation

DOI：

10.7507/1001-5515.202306011

Video：

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Targeting p21-activated kinase 1 (PAK1) is a novel strategy for pancreatic cancer treatment. Compound Kushen injection contains many anti-pancreatic cancer components, but the specific targets are unknown. In this study, 14α-hydroxymatrine, an active component of Kushen injection, was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening. Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket. Meanwhile, 14α-hydroxymatrine induced the β-folding region at the adenosine triphosphate (ATP)-binding pocket of PAK1 to close inward, resulting in the ATP-binding pocket in a “semi-closed” state which caused the inactivation of PAK1. After removal of 14α-hydroxymatrine, PAK1 showed a tendency to change from the inactive conformation to the active conformation. We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1. This study used modern technologies and methods to study the active components of traditional Chinese medicine, which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.

Citation： LIN Lin, CHANG Jingjie, TIAN Yaozhou, CHEN Jiao. Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1. Journal of Biomedical Engineering, 2024, 41(2): 313-320. doi: 10.7507/1001-5515.202306011 Copy

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15.	唐晓丽, 刘真君, 周鹏, 等. 复方苦参注射液联合GEMOX方案治疗中晚期胰腺癌临床疗效及对肿瘤标志物指标的影响. 湖北中医药大学学报, 2021, 23(2): 56-59.
16.	丛日楠, 乔建文. 复方苦参注射液联合放疗治疗晚期胰腺癌的近期疗效、安全性及对患者生活质量的影响. 现代中西医结合杂志, 2019, 28(12): 1335-1338.
17.	Zhou W, Huang Z, Wu C, et al. Investigation on the clinical efficacy and mechanism of compound kushen injection in treating esophageal cancer based on multi-dimensional network meta-analysis and in vitro experiment. J Ethnopharmacol, 2021, 279: 114386.
18.	Ur Rashid H, Rasool S, Ali Y, et al. Anti-cancer potential of sophoridine and its derivatives: recent progress and future perspectives. Bioorg Chem, 2020, 99: 103863.
19.	Cho Y R, Lee J H, Kim J H, et al. Matrine suppresses KRAS-driven pancreatic cancer growth by inhibiting autophagy-mediated energy metabolism. Mol Oncol, 2018, 12(7): 1203-1215.
20.	朱锦辉, 陈燕, 叶清煌, 等. 苦参碱对胰腺癌吉西他滨耐药及Aurora-A表达的影响. 浙江临床医学, 2016, 18(7): 1191-1193.
21.	Chen J, Yang J, Wei Q, et al. Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells. Cell Commun Signal, 2020, 18(1): 55.
22.	王鹏飞, 王京辉, 段秀梅, 等. HPLC法同时测定复方苦参注射液中7个成分含量及指纹图谱研究. 药物分析杂志, 2022, 42(7): 1101-1109.
23.	Karpov A S, Amiri P, Bellamacina C, et al. Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitor. ACS Med Chem Lett, 2015, 6(7): 776-781.
24.	Molli P R, Li D Q, Murray B W, et al. PAK signaling in oncogenesis. Oncogene, 2009, 28(28): 2545-2555.
25.	Liu T, Song Y, Chen H, et al. Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biol Pharm Bull, 2010, 33(10): 1740-1745.
26.	Ma Y, Zou F, Xiong J, et al. Effect of matrine on HPAC cell migration by down-regulating the expression of MT1-MMP via Wnt signaling. Cancer Cell Int, 2015, 15: 59.
27.	任丽平, 李先佳, 金少举. 槐定碱对人胰腺癌细胞株capan-1增殖及侵袭能力的影响. 河南科技大学学报: 医学版, 2016, 34(4): 244-246.

1. Rahib L, Smith B D, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014, 74(11): 2913-2921.
2. Zavoral M, Minarikova P, Zavada F, et al. Molecular biology of pancreatic cancer. World J Gastroenterol, 2011, 17(24): 2897-2908.
3. Yeo D, He H, Baldwin G S, et al. The role of p21-activated kinases in pancreatic cancer. Pancreas, 2015, 44(3): 363-369.
4. Jagadeeshan S, Krishnamoorthy Y R, Singhal M, et al. Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis. Oncogene, 2014, 34(4): 455-464.
5. Ye D Z, Field J. PAK signaling in cancer. Cell Logist, 2012, 2(2): 105-116.
6. Kumar R, Gururaj A E, Barnes C J. p21-activated kinases in cancer. Nat Rev Cancer, 2006, 6(6): 459-471.
7. Radu M, Semenova G, Kosoff R, et al. PAK signaling during the development and progression of cancer. Nat Rev Cancer, 2014, 14(1): 13-25.
8. Rudolph J, Crawford J J, Hoeflich K P, et al. Inhibitors of p21-activated kinases (PAKs). J Med Chem, 2015, 58(1): 111-129.
9. Wang J, Zhu Y, Chen J, et al. Identification of a novel PAK1 inhibitor to treat pancreatic cancer. Acta Pharmaceutica Sinica B, 2020, 10(4): 603-614.
10. Chauhan S C, Ebeling M C, Maher D M, et al. MUC13 mucin augments pancreatic tumorigenesis. Mol Cancer Ther, 2012, 11(1): 24-33.
11. Kimmelman A C, Hezel A F, Aguirre A J, et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci U S A, 2008, 105(49): 19372-19377.
12. Yeo D, Phillips P, Baldwin G S, et al. Inhibition of group 1 p21-activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer. Int J Cancer, 2017, 140(9): 2101-2111.
13. Yeo D, Hong H, Patel O, et al. FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer, 2016, 16: 24.
14. Yang Y, Sun M, Yao W, et al. Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib. J Immunother Cancer, 2020, 8(1): e000317.
15. 唐晓丽, 刘真君, 周鹏, 等. 复方苦参注射液联合GEMOX方案治疗中晚期胰腺癌临床疗效及对肿瘤标志物指标的影响. 湖北中医药大学学报, 2021, 23(2): 56-59.
16. 丛日楠, 乔建文. 复方苦参注射液联合放疗治疗晚期胰腺癌的近期疗效、安全性及对患者生活质量的影响. 现代中西医结合杂志, 2019, 28(12): 1335-1338.
17. Zhou W, Huang Z, Wu C, et al. Investigation on the clinical efficacy and mechanism of compound kushen injection in treating esophageal cancer based on multi-dimensional network meta-analysis and in vitro experiment. J Ethnopharmacol, 2021, 279: 114386.
18. Ur Rashid H, Rasool S, Ali Y, et al. Anti-cancer potential of sophoridine and its derivatives: recent progress and future perspectives. Bioorg Chem, 2020, 99: 103863.
19. Cho Y R, Lee J H, Kim J H, et al. Matrine suppresses KRAS-driven pancreatic cancer growth by inhibiting autophagy-mediated energy metabolism. Mol Oncol, 2018, 12(7): 1203-1215.
20. 朱锦辉, 陈燕, 叶清煌, 等. 苦参碱对胰腺癌吉西他滨耐药及Aurora-A表达的影响. 浙江临床医学, 2016, 18(7): 1191-1193.
21. Chen J, Yang J, Wei Q, et al. Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells. Cell Commun Signal, 2020, 18(1): 55.
22. 王鹏飞, 王京辉, 段秀梅, 等. HPLC法同时测定复方苦参注射液中7个成分含量及指纹图谱研究. 药物分析杂志, 2022, 42(7): 1101-1109.
23. Karpov A S, Amiri P, Bellamacina C, et al. Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitor. ACS Med Chem Lett, 2015, 6(7): 776-781.
24. Molli P R, Li D Q, Murray B W, et al. PAK signaling in oncogenesis. Oncogene, 2009, 28(28): 2545-2555.
25. Liu T, Song Y, Chen H, et al. Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biol Pharm Bull, 2010, 33(10): 1740-1745.
26. Ma Y, Zou F, Xiong J, et al. Effect of matrine on HPAC cell migration by down-regulating the expression of MT1-MMP via Wnt signaling. Cancer Cell Int, 2015, 15: 59.
27. 任丽平, 李先佳, 金少举. 槐定碱对人胰腺癌细胞株capan-1增殖及侵袭能力的影响. 河南科技大学学报: 医学版, 2016, 34(4): 244-246.

Journal of Biomedical Engineering

Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1

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