COMPUTATIONAL INVESTIGATION OF THE INHIBITION OF CHK1 AND WEE1 PROTEINS BY CHEMICAL CONSTITUENTS OF AMARANTHUS GANGETICUS

ADE S. ROHANI; HENNY S. WAHYUNI; EFFENDY DL PUTRA; NAZLINIWATY; CELINE AULETTA; TIARA RASYIDA

doi:10.22159/ijap.2025v17i5.53996

Authors

ADE S. ROHANI Department of Pharmaceutical Pharmacology, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia
HENNY S. WAHYUNI Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia https://orcid.org/0000-0002-7646-2928
EFFENDY DL PUTRA Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia
NAZLINIWATY Department of Pharmaceutical Technology, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia
CELINE AULETTA Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia
TIARA RASYIDA Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medan, Universitas Sumatera Utara, Indonesia

DOI:

https://doi.org/10.22159/ijap.2025v17i5.53996

Keywords:

Breast cancer, Red spinach (Amaranthus gangeticus) , CHK1, WEE1, In silico

Abstract

Objective: This study aimed to explore an alternative compound capable of inhibiting CHK1 (Checkpoint Kinase 1) and WEEl proteins in breast cancer using natural compounds derived from red spinach (Amaranthus gangeticus).

Methods: The experiment used SMILES and 3D structure of red spinach, PASS Online for biology activity, Lipinski's rule of five for physicochemical properties predictions, as well as validation, and molecular docking of active compounds.

Results: The results showed that CHK1 and WEE1 docking validation had RMSD values of 1.5 Å and 0.634 Å, respectively. The compounds 3,4,5-Trihydroxybenzoic acid, 3,5-Dimethoxy-4-hydroxybenzoic acid, 2,3,7,8-Tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 3-(3,4-Dihydroxycinnamoyl)quinic acid, 3-Methoxy-4-hydroxycinnamic acid, 4-Hydroxy-3,5-dimethoxycinnamic acid, 3-Phenylacrylic acid, 4′,5,7-Trihydroxyflavone, Catechin, and Quercetin exhibited favourable binding affinity values, molecular interactions, and predicted inhibitory effects against CHK1 by interacting with key residues LEU A 15, VAL A 23, and LEU A 137, and against WEE1 through interactions with GLU A 377, ILE A 305, VAL A 313, ALA A 326, and PHE A 433. While these findings highlight promising inhibitory potential, further in vitro and in vivo validation is needed to confirm the computational findings.

Conclusion: This study found that the active compounds of red spinach could be used as a functional inhibitor of CHK1 and WEE1.

References

1. Adam R, Dell Aquila K, Hodges L, Maldjian T, Duong TQ. Deep learning applications to breast cancer detection by magnetic resonance imaging: a literature review. Breast Cancer Res. 2023;25(1):87. doi: 10.1186/s13058-023-01687-4, PMID 37488621.

2. Sanganna B, Chitme HR, Vrunda K, Jamadar MJ. Antiproliferative and antioxidant activity of leaves extracts of Moringa oleifera. Int J Curr Pharm Sci. 2016 Oct 18;8(4):54. doi: 10.22159/ijcpr.2016v8i4.15278.

3. Elias A, Habbu PV, Iliger S. Preparation, characterization and screening of silver nanoparticles using phenolic-rich fractions of Amaranthus gangeticus L. for its in vitro antioxidant anti-diabetic and anticancer activities. RGUHS J Pharm Sci. 2021;11(3):32-8. doi: 10.26463/rjps.11_3_5.

4. Junedi S, Hermawan A, Fitriasari A, Setiawati A, Susidarti RA, Meiyanto E. The doxorubicin-induced induced G2/M arrest in breast cancer cells modulated by natural compounds naringenin and hesperidin. Indones J Cancer Chemoprevent. 2021 Oct 18;12(2):83-9. doi: 10.14499/indonesianjcanchemoprev12iss2pp83-89.

5. Dey S, Roychoudhury R, Malakar S, Sarkar R. Screening of breast cancer from thermogram images by edge detection aided deep transfer learning model. Multimed Tools Appl. 2022 Jan 8;81(7):9331-49. doi: 10.1007/s11042-021-11477-9, PMID 35035264.

6. Lukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanislawek A. Breast cancer epidemiology risk factors, classification prognostic markers and current treatment strategies an updated review. Cancers. 2021 Aug 25;13(17):4287. doi: 10.3390/cancers13174287, PMID 34503097.

7. Solikhah S, Promthet S, Hurst C. Awareness level about breast cancer risk factors barriers, attitude and breast cancer screening among Indonesian Women. Asian Pac J Cancer Prev. 2019 Mar 26;20(3):877-84. doi: 10.31557/APJCP.2019.20.3.877, PMID 30912407.

8. Tavani A, La Vecchia C. Fruit and vegetable consumption and cancer risk in a mediterranean population. Am J Clin Nutr. 1995;61(6)Suppl:1374S-7S. doi: 10.1093/ajcn/61.6.1374S, PMID 7754990.

9. Sani HA, Rahmat A, Ismail M, Rosli R, Endrini S. Potential anticancer effect of red spinach (Amaranthus gangeticus) extract. Asia Pac J Clin Nutr. 2004;13(4):396-400. PMID 15563447.

10. Zhu L, Xue L. Kaempferol suppresses proliferation and induces cell cycle arrest apoptosis and DNA damage in breast cancer cells. Oncol Res. 2019 Jun 21;27(6):629-34. doi: 10.3727/096504018X15228018559434, PMID 29739490.

11. Song W, Dang Q, Xu D, Chen Y, Zhu G, Wu K. Kaempferol induces cell cycle arrest and apoptosis in renal cell carcinoma through EGFR/p38 signaling. Oncol Rep. 2014;31(3):1350-6. doi: 10.3892/or.2014.2965, PMID 24399193.

12. Bruyer A, Dutrieux L, De Boussac H, Martin T, Chemlal D, Robert N. Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma. Front Oncol. 2023 Dec 6;13:1271847. doi: 10.3389/fonc.2023.1271847, PMID 38125947.

13. Song X, Wang L, Wang T, Hu J, Wang J, Tu R. Synergistic targeting of CHK1 and mTOR in MYC-driven tumors. Carcinogenesis. 2021 Apr 17;42(3):448-60. doi: 10.1093/carcin/bgaa119, PMID 33206174.

14. Ghelli Luserna Di Rorà AG, Bocconcelli M, Ferrari A, Terragna C, Bruno S, Imbrogno E. Synergism through WEE1 and CHK1 inhibition in acute lymphoblastic leukemia. Cancers. 2019 Oct 25;11(11):1654. doi: 10.3390/cancers11111654, PMID 31717700.

15. Cole KA, Pal S, Kudgus RA, Ijaz H, Liu X, Minard CG. Phase I clinical trial of the Wee1 inhibitor adavosertib (AZD1775) with irinotecan in children with relapsed solid tumors: a COG phase I consortium report (ADVL1312). Clin Cancer Res. 2020;26(6):1213-9. doi: 10.1158/1078-0432.CCR-19-3470, PMID 31857431.

16. Liu JF, Xiong N, Campos SM, Wright AA, Krasner CN, Schumer ST. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. J Clin Oncol. 2020;38(15Suppl):6009. doi: 10.1200/JCO.2020.38.15_suppl.6009.

17. Cash T, Fox E, Liu X, Minard CG, Reid JM, Scheck AC. A phase 1 study of prexasertib (LY2606368) a CHK1/2 inhibitor in pediatric patients with recurrent or refractory solid tumors including CNS tumors: a report from the childrens oncology group pediatric early phase clinical trials network (ADVL1515). Pediatr Blood Cancer. 2021;68(9):e29065. doi: 10.1002/pbc.29065.

18. Konstantinopoulos PA, Lee JM, Gao B, Miller R, Lee JY, Colombo N. A phase 2 study of prexasertib (LY2606368) in platinum-resistant or refractory recurrent ovarian cancer. Gynecol Oncol. 2022;167(2):213-25. doi: 10.1016/j.ygyno.2022.09.019, PMID 36192237.

19. Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep. 2023 Aug 17;13(1):13398. doi: 10.1038/s41598-023-40160-2, PMID 37592012.

20. Trott O, Olson AJ. Autodock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010 Jan 30;31(2):455-61. doi: 10.1002/jcc.21334, PMID 19499576.

21. Dassault systemes. BIOVIA Discovery Studio Visualizer; 2016.

22. Schrodinger LL. The PyMOL molecular graphics system. Version 2.5; 2015.

23. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0, PMID 11259830.

24. Lagunin A, Stepanchikova A, Filimonov D, Poroikov V. Pass: prediction of activity spectra for biologically active substances. Bioinformatics. 2000;16(8):747-8. doi: 10.1093/bioinformatics/16.8.747, PMID 11099264.

25. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H. The protein data bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. doi: 10.1093/nar/28.1.235, PMID 10592235.

26. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A. Pubchem substance and compound databases. Nucleic Acids Res. 2016 Jan 4;44(D1):D1202-13. doi: 10.1093/nar/gkv951, PMID 26400175.

27. Kalanjati V, Pratiwi MP, Syakdiyah NH, Widiasi ED, Anggraeni MR, Pratiwi IA. Pengaruh ekstrak bayam merah (Amaranthus gangeticus) terhadap morfologi stratum hipokampus model anak mencit pascasapih induk yang terpapar timbal selama masa kehamilan. MKB. 2014;46(3):125-9. doi: 10.15395/mkb.v46n3.116.

28. Sarker U, Ercisli S. Salt eustress induction in red amaranth (Amaranthus gangeticus) augments nutritional phenolic acids and antiradical potential of leaves. Antioxidants (Basel). 2022 Dec 9;11(12):2434. doi: 10.3390/antiox11122434, PMID 36552642.

29. Sarker U, Oba S. Color attributes betacyanin and carotenoid profiles bioactive components and radical quenching capacity in selected Amaranthus gangeticus leafy vegetables. Sci Rep. 2021 Jun 2;11(1):11559. doi: 10.1038/s41598-021-91157-8, PMID 34079029.

30. Sarker U, Oba S. Polyphenol and flavonoid profiles and radical scavenging activity in leafy vegetable Amaranthus gangeticus. BMC Plant Biol. 2020 Nov 2;20(1):499. doi: 10.1186/s12870-020-02700-0, PMID 33138787.

31. Matin MM, Roshid MH, Bhattacharjee SC, Azad AK. Pass predication antiviral in vitro antimicrobial and ADMET studies of rhamnopyranoside esters. Med Res Arch. 2020 Jul 22;8(7):1-13. doi: 10.18103/mra.v8i7.2165.

32. Elias A, Habbu PV, Iliger S. Preparation characterization and screening of gold nanoparticles using phenolic-rich fractions of Amaranthus gangeticus L. for its in vitro antioxidant, anti-diabetic and anti-cancer activities. J Pharm Res Int. 2021;33(57A):425-39. doi: 10.9734/jpri/2021/v33i57A34016.

33. Roskoski R. Rule of five violations among the FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2023;191:106774. doi: 10.1016/j.phrs.2023.106774, PMID 37075870.

34. VM. In silico molecular screening and docking approaches on antineoplastic agent irinotecan towards the marker proteins of colon cancer. Int J Appl Pharm VP. 2023;15(5):84-92. doi: 10.22159/ijap.2023v15i5.48523.

35. Shamsian S, Sokouti B, Dastmalchi S. Benchmarking different docking protocols for predicting the binding poses of ligands complexed with cyclooxygenase enzymes and screening chemical libraries. BioImpacts. 2024;14(2):29955. doi: 10.34172/bi.2023.29955, PMID 38505677.

36. Nguyen NT, Nguyen TH, Pham TN, Huy NT, Bay MV, Pham MQ. Autodock vina adopts more accurate binding poses but Autodock4 forms better binding affinity. J Chem Inf Model. 2020 Jan 27;60(1):204-11. doi: 10.1021/acs.jcim.9b00778, PMID 31887035.

37. Yin K, Zhao G, Xu C, Qiu X, Wen B, Sun H. Prediction of Toxoplasma gondii virulence factor ROP18 competitive inhibitors by virtual screening. Parasit Vectors. 2019 Mar 13;12(1):98. doi: 10.1186/s13071-019-3341-y, PMID 30867024.

38. Squire CJ, Dickson JM, Ivanovic I, Baker EN. Structure and inhibition of the human cell cycle checkpoint kinase WEE1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation. Structure. 2005;13(4):541-50. doi: 10.1016/j.str.2004.12.017, PMID 15837193.