Skip to main content
SpringerLink
Log in

Acetogenins as potential checkpoint-2 kinase inhibitors: an in silico analysis

  • Short Communication
  • Published:
Journal of Proteins and Proteomics Aims and scope Submit manuscript

Abstract

Acetogenins are known anticancer agents present in the family Annonaceae. Drugs which can downregulate checkpoint kinase 2 (CHK2) in the ataxia telangiectasia mutated (ATM) signaling pathway are known to enhance chemosensitizing and radiosensitizing effects in cancer therapy. In the present study, the effect of 20 acetogenin compounds on CHK2 kinase is evaluated using Molecular docking studies. Twenty different acetogenin structures were retrieved from Pubchem. The physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) were predicted. In silico virtual screening simulation was performed against CHK2 kinase. Among the 20 acetogenin compounds, Glabracin A showed the highest binding energy of − 14.9 kcal/mol. All the other acetogenins showed good binding energy of − 6.4 to − 7.4 kcal/mol with at least one or more hydrogen bonds. In silico analysis evidences acetogenins as good CHK2 inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  • Albarakati N, Abdel-Fatah T, Doherty R, Russell R, Agarwal D, Moseley P et al (2015) Targeting BRCA1 BER deficient breast cancer by ATM or DNA PKcs blockade either alone or in combination with cisplatin for personalized therapy. Mol Oncol 9(1):204–217

    Article  CAS  PubMed  Google Scholar 

  • Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11:726–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berman H, Henrick K, Nakamura H (2003) Announcing the worldwide protein data bank. Nat Struct Mol Biol 10(12):980

    Article  CAS  Google Scholar 

  • Bolton EE, Wang Y, Thiessen PA, Bryant SH (2008) PubChem: integrated platform of small molecules and biological activities. Annu Rep Comput Chem 4:217–241

    Article  CAS  Google Scholar 

  • Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G et al (2012) admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 52:3099–3105

    Article  CAS  PubMed  Google Scholar 

  • Chih HW, Chiu HF, Tang KS, Chang FR, Wu YC (2001) Bullatacin, a potent antitumor annonaceous acetogenin, inhibits proliferation of human hepatocarcinoma cell line 2.2. 15 by apoptosis induction. Life Sci 69(11):1321–1331

    Article  CAS  PubMed  Google Scholar 

  • Coothankandaswamy V, Liu Y, Mao SC, Morgan JB, Mahdi F, Jekabsons MB et al (2010) The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway. J Nat Prod 73(5):956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dallakyan S, Olson AJ (2015) Small-molecule library screening by docking with PyRx. Methods Mol Bio 1263:243–250

    Article  CAS  Google Scholar 

  • Deep G, Kumar R, Jain AK, Dhar D, Panigrahi GK, Hussain A et al (2016) Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci Rep 6:23135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeLano WL (2002) ThePyMOL molecular graphics system. DeLano Scientific, San Carlos, CA, USA. http://www.pymol.org. Accessed 10 Oct 2014

  • Duong HQ, Hong YB, Kim JS, Lee HS, Yi YW, Kim YJ et al (2013) Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. J Cell Mol Med 17(10):1261–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • González-Coloma A, Guadano A, Inés CD, Martínez-Díaz R, Cortes D (2002) Selective action of acetogenin mitochondrial complex I inhibitors. Z Naturforsch C 57(11–12):1028–1034

    Article  PubMed  Google Scholar 

  • Hacker K, Maas R, Kornhuber J, Fromm MF, Zolk O (2015) Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PloS One 10(9):e0136451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He K, Zhao GX, Shi G, Zeng L, Chao JF, McLaughlin JL (1997) Additional bioactive annonaceous acetogenins from Asimina triloba (Annonaceae). Bioorg Med Chem 5(3):501–506

    Article  CAS  PubMed  Google Scholar 

  • Jabeen I, Pleban K, Rinner U, Chiba P, Ecker GF (2012) Structure–activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P-glycoprotein. J Med Chem 55(7):3261–3273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamkhande PG, Wattamwar AS (2015) Annona reticulata Linn (Bullock’s heart): plant profile, phytochemistry and pharmacological properties. J Tradit Complement Med 5(3):144–152

    Article  PubMed  PubMed Central  Google Scholar 

  • Jobson AG, Cardellina JH, Scudiero D, Kondapaka S, Zhang H, Kim H et al (2007) Identification of a Bis-guanylhydrazone [4, 4′-Diacetyldiphenylurea-bis (guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase. Mol Pharmacol 72(4):876–884

    Article  CAS  PubMed  Google Scholar 

  • Keserü GM, Makara GM (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discovery 8(3):203

    Article  PubMed  CAS  Google Scholar 

  • Kojima N, Tanaka T (2009) Medicinal chemistry of Annonaceous acetogenins: design, synthesis, and biological evaluation of novel analogues. Molecules 14(9):3621–3661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larregieu CA, Benet LZ (2013) Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements. AAPS J 15(2):483–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51(10):2778–2786

    Article  CAS  PubMed  Google Scholar 

  • Liaw CC, Chang FR, Wu MJ, Wu YC (2003) A novel constituent from Rollinia mucosa, Rollicosin, and a new approach to develop annonaceous acetogenins as potential antitumor agents. J Nat Prod 66(2):279–281

    Article  CAS  PubMed  Google Scholar 

  • Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341

    Article  CAS  PubMed  Google Scholar 

  • Liu XX, Alali FQ, Hopp DC, Rogers LL, Pilarinou E, McLaughlin JL (1998) Glabracins A and B, two new acetogenins from Annona glabra. Bioorg Med Chem 6(7):959–965

    Article  CAS  PubMed  Google Scholar 

  • Matthews TP, Jones AM, Collins I (2013) Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin Drug Discov 8(6):621–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng XY, Zhang HX, Mezei M, Cui M (2011) Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des 7(2):146–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moghadamtousi SZ, Rouhollahi E, Karimian H, Fadaeinasab M, Firoozinia M, Abdulla MA et al (2015) The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of acetogenin annomuricin E in HT-29 cells: a bioassay-guided approach. PloS One 10(4):e0122288

    Article  CAS  Google Scholar 

  • Pettit GR, Riesen R, Leet JE, Polonsky J, Smith CR, Schmidt JM, Dufresne C, Schaufelberger D, Moretti C (1989) Isolation and structure of rolliniastatin 2: a new cell growth inhibitory acetogenin from rollznza mucosa1. Heterocycles 28(7)

  • Pires IM, Ward TH, Dive C (2010) Oxaliplatin responses in colorectal cancer cells are modulated by CHK2 kinase inhibitors. Br J Pharmacol 159(6):1326–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pommier Y, Weinstein JN, Aladjem MI, Kohn KW (2006) Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clin Cancer Res 12(9):2657–2661

    Article  CAS  PubMed  Google Scholar 

  • Qayed WS, Aboraia AS, Abdel-Rahman HM, Youssef AF (2015) Annonaceous acetogenins as a new anticancer agent. Der Pharma Chemica 7(6):24–35

    CAS  Google Scholar 

  • Ragasa CY, Soriano G, Torres OB, Don MJ, Shen CC (2012) Acetogenins from Annona muricata. Pharmacognosy J 4(32):32–37

    Article  CAS  Google Scholar 

  • Sander T, Freyss J, von Korff M, Rufener C (2015) DataWarrior: an open-source program for chemistry aware data visualization and analysis. J Chem Inf Model 55(2):460–473

    Article  CAS  PubMed  Google Scholar 

  • Schüttelkopf AW, Van Aalten DMF (2004) PRODRG—a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D60:1355–1363

    Google Scholar 

  • Sevrioukova IF, Poulos TL (2015) Current approaches for investigating and predicting cytochrome P450 3A4-ligand interactions. Monooxygenase, peroxidase and peroxygenase properties and mechanisms of cytochrome P450. Springer International Publishing, Cham, pp 83–105

    Chapter  Google Scholar 

  • Shepard PD, Canavier CC, Levitan ES (2007) Ether-a-go-go–related gene potassium channels: what’s all the buzz about? Schizophr Bull 33(6):1263–1269

    Article  PubMed  PubMed Central  Google Scholar 

  • Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C et al (2013) Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. PloS One 8(6):e65689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sjögren E, Helena T, Christer T (2016) In silico modeling of gastrointestinal drug absorption: predictive performance of three physiologically based absorption models. Mol Pharm 13(6):1763–1778

    Article  PubMed  CAS  Google Scholar 

  • Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED et al (2012) Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett 323(1):29–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsaioun K, Blaauboer BJ, Hartung T (2016) Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX 33(4):343

    Article  PubMed  Google Scholar 

  • Veerakumar S, Amanulla SS, Ramanathan K (2016) Anti-cancer efficacy of ethanolic extracts from various parts of Annona Squamosa on MCF-7 cell line. J Pharmacogn Phytother 8(7):147–154

    Article  CAS  Google Scholar 

  • Velic D, Couturier AM, Ferreira MT, Rodrigue A, Poirier GG, Fleury F, Masson JY (2015) DNA damage signalling and repair inhibitors: the long-sought-after Achilles’ heel of cancer. Biomolecules 5(4):3204–3259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vijesh AM, Isloor AM, Telkar S, Arulmoli T, Fun HK (2013) Molecular docking studies of some new imidazole derivatives for antimicrobial properties. Arab J Chem 6(2):197–204

    Article  CAS  Google Scholar 

  • Wessler JD et al (2013) The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 61(25):2495–2502

    Article  CAS  PubMed  Google Scholar 

  • Wu FE, Zhao GX, Zeng L, Zhang Y, Schwedler JT, McLaughlin JL, Sastrodihardjo S (1995) Additional bioactive acetogenins, annomutacin and (2, 4-trans and cis)-10R-annonacin-A-ones, from the leaves of Annona muricata. J Nat Prod 58(9):1430–1437

    Article  CAS  PubMed  Google Scholar 

  • Xu L, Chang CJ, Yu JG, Cassady JM (1989) Chemistry and selective cytotoxicity of annonacin-10-one, isoannonacin, and isoannonacin-10-one. Novel polyketides from Annona densicoma (Annonaceae). J Org Chem 54(23):5418–5421

    Article  CAS  Google Scholar 

  • Yang H, Zhang N, Li X, Chen J, Cai B (2009) Structure–activity relationships of diverse annonaceous acetogenins against human tumor cells. Bioorg Med Chem Lett 19(8):2199–2202

    Article  PubMed  CAS  Google Scholar 

  • Ye Q, He K, Oberlies NH, Zeng L, Shi G, Evert D, McLaughlin JL (1996) Longimicins A−D: Novel bioactive acetogenins from Asimina longifolia (Annonaceae) and structure−activity relationships of asimicin type of Annonaceous acetogenins. J Med Chem 39(9):1790–1796

    Article  CAS  PubMed  Google Scholar 

  • Yuan SS, Chang HL, Chen HW, Yeh YT, Kao YH, Lin KH, Wu YC, Su JH (2003) Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax-and caspase-3-related pathway. Life Sci 72(25):2853–2861

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Xie G, Yan X (2011) Encyclopedia of traditional Chinese medicines. Isolat Compound AB 1:455

    Google Scholar 

Download references

Acknowledgements

All the authors thank Department of Biotechnology, Kuvempu University for providing the facilities to carry out the research work. The first author acknowledges the Department of Science and Technology, Women Scientist Scheme-A Grant No. SR/WOS-A/LS/461/2016(G) for financial support.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Kuvempu University, Shankarghatta, Karnataka, 577451, India

    P. Meghana, Jain R. Sandeep Kumar, Telkar Sandeep, N. Prashanth & H. M. Kumaraswamy

Authors
  1. P. Meghana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jain R. Sandeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Telkar Sandeep
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Prashanth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. M. Kumaraswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. M. Kumaraswamy.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meghana, P., Sandeep Kumar, J.R., Sandeep, T. et al. Acetogenins as potential checkpoint-2 kinase inhibitors: an in silico analysis. J Proteins Proteom 10, 299–311 (2019). https://doi.org/10.1007/s42485-019-00025-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42485-019-00025-7

Keywords

Search

Navigation