Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic studies, molecular docking, and molecular dynamics simulations of phytochemicals from Morus alba: a multi receptor approach for potential therapeutic agents in colorectal cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

This study explores the therapeutic potential of phytochemicals derived from Morus alba for colorectal cancer (CRC) treatment. Colorectal cancer is a global health concern with increasing mortality rates, necessitating innovative strategies for prevention and therapy. Employing in silico analysis, molecular docking techniques (MDT), and molecular dynamics simulations (MDS), the study investigates the interactions between Morus alba-derived phytochemicals and key proteins (AKT1, Src, STAT3, EGFR) implicated in CRC progression. ADME/T analysis screens 78 phytochemicals for drug-like and pharmacokinetic properties. The study integrates Lipinski’s Rule of Five and comprehensive bioactivity assessments, providing a nuanced understanding of Morus alba phytoconstituent’s potential as CRC therapeutic agents. Notably, 14 phytochemicals out of 78 emerge as potential candidates, demonstrating oral bioavailability and favorable bioactivity scores. Autodock 1.5.7 is employed for energy minimization followed by molecular docking with the highest binding energy observed to be − 11.7 kcal/mol exhibited by Kuwanon A against AKT1. Molecular dynamics simulations and trajectory path analysis were conducted between Kuwanon A and AKT1 at the Pleckstrin homology (PH) domain region (TRP80), revealing minimal deviations. In comparison to the standard drug Capivasertib, the phytochemical Kuwanon A emerges as a standout candidate based on computational analysis. This suggests its potential as an alternative to mitigate the limitations associated with the standard drug. The research aims to provide insights for future experimental validations and to stimulate the development of Kuwanon A as a novel, effective therapeutic agent for managing colorectal cancer.

Graphical abstract

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Upon request, the data will be made accessible.

Code availability

Not applicable.

Abbreviations

CRC:

Colorectal cancer

PH:

Pleckstrin homology

HDI:

Human development index

AKT:

Serine/Threonine protein kinase

STAT3:

Signal transducer and activator of transcription 3

EGFR:

Epidermal Growth Factor Receptor

Src:

Protooncogene Tyrosine Protein Kinase

DNJ:

1-Deoxynojirimycin

MEMA:

Morus alba L. root bark extract

SREBF2:

Sterol regulatory element binding transcription factor 2

FOXO3a:

Morusinol facilitated forkhead box O3

MDT:

Molecular docking techniques

MDS:

Molecular dynamics simulations

RMSD:

Root mean square deviation

MW:

Molecular weight

NHA:

Number of hydrogen bond acceptor

NHD:

Number of hydrogen bond donor

NRB:

Number of rotatable bonds

TPSA:

Total polar surface area

NVT:

Number of molecules, volume, temperature

NPT:

Number of molecules, pressure, temperature

VMD:

Visual Molecular dynamics

References

  1. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE. A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13092025.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2016. https://doi.org/10.1136/gutjnl-2015-310912.

    Article  PubMed  Google Scholar 

  3. Douaiher J, Ravipati A, Grams B, Chowdhury S, Alatise O, Are C. Colorectal cancer—global burden, trends, and geographical variations. J Surg Oncol. 2017;115:619–30.

    Article  PubMed  Google Scholar 

  4. Wong MCS, Huang J, Lok V, Wang J, Fung F, Ding H, et al. Differences in incidence and mortality trends of colorectal cancer worldwide based on sex, age, and anatomic location. Clin Gastroenterol Hepatol. 2021;19:955–66.

    Article  PubMed  Google Scholar 

  5. Hossain MS, Karuniawati H, Jairoun AA, Urbi Z, Ooi DJ, John A, et al. Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers (Basel). 2022. https://doi.org/10.3390/cancers14071732.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P. Smoking and colorectal cancer: a meta-analysis. JAMA. 2008;300:2765–78.

    Article  CAS  PubMed  Google Scholar 

  7. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose–response meta-analysis. Br J Cancer. 2015;112:580–93.

    Article  CAS  PubMed  Google Scholar 

  8. Freisling H, Arnold M, Soerjomataram I, O’Doherty MG, Ordóñez-Mena JM, Bamia C, et al. Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe. Br J Cancer. 2017;116:1486–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vieira AR, Abar L, Chan DSM, Vingeliene S, Polemiti E, Stevens C, et al. Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project. Ann Oncol. 2017;28:1788–02.

    Article  CAS  PubMed  Google Scholar 

  10. C NCG. National institute for health and care excellence: clinical guidelines. Chronic Kidney Dis. (Partial Updat. Early Identif. Manag. Chronic Kidney Dis. Adults Prim. Second. Care. National Institute for Health and Care Excellence (UK) Copyright{\copyright} National~…; 2014. p. 2014.

  11. suspected cancer | Search results | NICE [Internet]. [cited 2024 Jan 29]. Available from: https://www.nice.org.uk/search?q=suspected+cancer&gst=Published

  12. Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJY, Young GP, et al. Colorectal cancer screening: a global overview of existing programmes. Gut. 2015. https://doi.org/10.1136/gutjnl-2014-309086.

    Article  PubMed  Google Scholar 

  13. Hua H, Zhang H, Chen J, Wang J, Liu J, Jiang Y. Targeting Akt in cancer for precision therapy. J Hematol Oncol. 2021;14:128. https://doi.org/10.1186/s13045-021-01137-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jin W. Regulation of Src family kinases during colorectal cancer development and its clinical implications. Cancers (Basel). 2020. https://doi.org/10.3390/cancers12051339.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lin Y, He Z, Ye J, Liu Z, She X, Gao X, et al. Progress in understanding the IL-6/STAT3 pathway in colorectal cancer. Onco Targets Ther. 2020;13:13023–32. https://doi.org/10.2147/OTT.S278013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lawal B, Wang Y-C, Wu ATH, Huang H-S. Pro-oncogenic c-Met/EGFR, biomarker signatures of the tumor microenvironment are clinical and therapy response prognosticators in colorectal cancer, and therapeutic targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives. Front Pharmacol. 2021. https://doi.org/10.3389/fphar.2021.691234.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Atanasov AG, Waltenberger B, Pferschy-Wenzig E-M, Linder T, Wawrosch C, Uhrin P, et al. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv. 2015;33:1582–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hussain F, Rana Z, Shafique H, Malik A, Hussain Z. Phytopharmacological potential of different species of Morus alba and their bioactive phytochemicals: A review. Asian Pac J Trop Biomed. 2017;7:950–6.

    Article  Google Scholar 

  19. Khan T, Ali M, Khan A, Nisar P, Jan SA, Afridi S, et al. Anticancer plants: a review of the active phytochemicals, applications in animal models, and regulatory aspects. Biomolecules. 2019. https://doi.org/10.3390/biom10010047.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yamamoto K, Sakamoto Y, Mizowaki Y, Iwagaki Y, Kimura T, et al. Intake of mulberry 1-deoxynojirimycin prevents colorectal cancer in mice. J Clin Biochem Nutr. 2017;61:47–52.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Park H-J, Park S-H. Root bark of Morus alba L. Induced p53-independent apoptosis in human colorectal cancer cells by suppression of STAT3 activity. Nutr Cancer. 2022;74:1837–48. https://doi.org/10.1080/01635581.2021.1968444.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang X, Dong Z, Yang Y, Liu C, Li J, Sun W, et al. Morusinol extracted from Morus alba inhibits cell proliferation and induces autophagy via FOXO3a nuclear accumulation-mediated cholesterol biosynthesis obstruction in colorectal cancer. J Agric Food Chem. 2023;71:16016–31.

    Article  CAS  PubMed  Google Scholar 

  23. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC. GROMACS: Fast, flexible, and free. J Comput Chem. 2005;26:1701–18. https://doi.org/10.1002/jcc.20291.

    Article  CAS  PubMed  Google Scholar 

  24. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1:337–41.

    Article  CAS  PubMed  Google Scholar 

  25. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. https://doi.org/10.1038/srep42717.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Daina A, Zoete V. A BOILED-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016;11:1117–21. https://doi.org/10.1002/cmdc.201600182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013. https://doi.org/10.33393/dti.2013.1349.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rong S-B, Hu Y, Enyedy I, Powis G, Meuillet EJ, Wu X, et al. Molecular modeling Studies of the Akt PH Domain and Its Interaction with phosphoinositides. J Med Chem. 2001;44:898–908. https://doi.org/10.1021/jm000493i.

    Article  CAS  PubMed  Google Scholar 

  29. Banerji U, Dean EJ, Pérez-Fidalgo JA, Batist G, Bedard PL, You B, et al. A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-Mutated breast and gynecologic cancers. Clin Cancer Res. 2018;24:2050–9. https://doi.org/10.1158/1078-0432.CCR-17-2260.

    Article  CAS  PubMed  Google Scholar 

  30. Su J, Thakur A, Pan G, Yan J, Gaurav I, Thakur S, et al. Morus alba derived Kuwanon-A combined with 5-fluorouracil reduce tumor progression via synergistic activation of GADD153 in gastric cancer. MedComm – Oncol. 2023;2:e24. https://doi.org/10.1002/mog2.24.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to Vellore Institute of Technology, Vellore for providing research facilities in School of Bio-Sciences and Technology.

Funding

Not applicable.

Author information

Author notes

  1. B. Stany and Shatakshi Mishra shares first authors.

Authors and Affiliations

  1. School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India

    B. Stany & Shatakshi Mishra

  2. Marine Biotechnology Laboratory, Department of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India

    K. V. Bhaskara Rao

Authors
  1. B. Stany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shatakshi Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. V. Bhaskara Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BS, SM, and KVBR conceptualized and orchestrated the research, contributing to its design. BS, SM, and KVBR conducted the experimental procedures and collaborated on drafting the manuscript. All authors meticulously reviewed and granted their approval for the final manuscript.

Corresponding author

Correspondence to K. V. Bhaskara Rao.

Ethics declarations

Competing interest

The authors have no conflicts of interest to disclose.

Ethical approval

Not applicable.

Consent to participant

Not applicable.

Consent to publication

All authors meticulously reviewed.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 22795 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stany, B., Mishra, S. & Rao, K.V.B. Pharmacokinetic studies, molecular docking, and molecular dynamics simulations of phytochemicals from Morus alba: a multi receptor approach for potential therapeutic agents in colorectal cancer. Med Oncol 41, 156 (2024). https://doi.org/10.1007/s12032-024-02406-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-024-02406-5

Keywords

Search

Navigation