Skip to main content

Advertisement

SpringerLink
Log in

Repurposing of Strychnine as the Potential Inhibitors of Aldo–keto Reductase Family 1 Members B1 and B10: Computational Modeling and Pharmacokinetic Analysis

  • Published:
The Protein Journal Aims and scope Submit manuscript

Abstract

AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule’s reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

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
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19
Fig. 20

Similar content being viewed by others

Availability of Data and Materials

Data will be available on request by the corresponding author.

References

  1. Juliusson G, Lazarevic V, Hörstedt AS, Hagberg O, Höglund M (2012) Acute myeloid leukemia in the real world: why population-based registries are needed. Blood J Am Soc Hematol 119(17):3890–3899

    CAS  Google Scholar 

  2. Hussen BM, Hidayat HJ, Salihi A, Sabir DK, Taheri M, Ghafouri-Fard S (2021) MicroRNA: a signature for cancer progression. Biomed Pharmacother 138:111528

    Article  CAS  PubMed  Google Scholar 

  3. Penning TM (2015) The aldo-keto reductases (AKRs): overview. Chem Biol Interact 234:236–246

    Article  CAS  PubMed  Google Scholar 

  4. Giménez-Dejoz J, Weber S, Fernández-Pardo Á, Möller G, Adamski J, Porté S, Parés X, Farrés J (2019) Engineering aldo-keto reductase 1B10 to mimic the distinct 1B15 topology and specificity towards inhibitors and substrates, including retinoids and steroids. Chem Biol Interact 307:186–194

    Article  PubMed  Google Scholar 

  5. Munkácsy G, Santarpia L, Győrffy B (2023) Therapeutic potential of tumor metabolic reprogramming in triple-negative breast cancer. Int J Mol Sci 24(8):6945

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sun T, Liu Z, Yang Q (2020) The role of ubiquitination and deubiquitination in cancer metabolism. Mol Cancer 19:1–19

    Article  Google Scholar 

  7. Taskoparan B, Seza EG, Demirkol S, Tuncer S, Stefek M, Gure AO, Banerjee S (2017) Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer. Cell Oncol 40:563–578

    Article  CAS  Google Scholar 

  8. Kropotova ES, Tychko RA, Zinov’eva OL, Zyryanova AF, Khankin SL, Cherkes VL, Aliev VA, Beresten SF, Oparina NY, Mashkova TD (2010) Downregulation of AKR1B10 expression in colorectal cancer. Mol Biol 44:216–222

    Article  CAS  Google Scholar 

  9. Chen B, Garmire L, Calvisi DF, Chua MS, Kelley RK, Chen X (2020) Harnessing big ‘omics’ data and AI for drug discovery in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 17(4):238–251

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sravanthi TV, Manju SL (2016) Indoles—a promising scaffold for drug development. Eur J Pharm Sci 91:1–10

    Article  CAS  PubMed  Google Scholar 

  11. Sharma V, Kumar P, Pathak D (2010) Biological importance of the indole nucleus in recent years: a comprehensive review. J Heterocycl Chem 47(3):491–502

    Article  CAS  Google Scholar 

  12. Lauria A, Delisi R, Mingoia F, Terenzi A, Martorana A, Barone G, Almerico AM (2014) 1, 2, 3-Triazole in heterocyclic compounds, endowed with biological activity, through 1, 3-dipolar cycloadditions. Eur J Org Chem 2014(16):3289–3306

    Article  CAS  Google Scholar 

  13. Saraswati S, Mathur R, Agrawal SS (2010) 653 Evaluation of strychnine, a plant alkaloid for in vitro antiangiogenesis, apoptosis and antioxidant potential in MCF-7 cancer cells. EJC Suppl 7(8):204

    Article  Google Scholar 

  14. Song Y, Yang J, Yu J, Li J, Yuan J, Wong NK, Ju J (2020) Chlorinated bis-indole alkaloids from deep-sea derived Streptomyces sp. SCSIO 11791 with antibacterial and cytotoxic activities. J Antibiot 73(8):542–547

    Article  CAS  Google Scholar 

  15. Ruiz FX, Cousido-Siah A, Mitschler A, Farres J, Pares X, Podjarny A (2013) X-ray structure of the V301L aldo–keto reductase 1B10 complexed with NADP+ and the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivity. Chem Biol Interact 202(1–3):178–185

    Article  CAS  PubMed  Google Scholar 

  16. Zhang L, Zhang H, Zhao Y, Li Z, Chen S, Zhai J, Chen Y, Xie W, Wang Z, Li Q, Zheng X (2013) Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: role of Trp112 (Trp111). FEBS Lett 587(22):3681–3686

    Article  CAS  PubMed  Google Scholar 

  17. Huang L, He R, Luo W, Zhu YS, Li J, Tan T, Zhang X, Hu Z, Luo D (2016) Aldo-keto reductase family 1 member B10 inhibitors: potential drugs for cancer treatment. Recent Pat Anti-Cancer Drug Discovery 11(2):184–196

    Article  CAS  PubMed  Google Scholar 

  18. Foulani AAE, Hammoudan I, Byoud F, Jamal-eddine J, Lekhlif B (2022) Synthesis, characterization, and evaluation of new composites coagulants polyaluminum chloride-sodium alginate. Water Air Soil Pollut 233(8):301

    Article  CAS  Google Scholar 

  19. Gaussian RA (2009) 1, mj frisch, gw trucks, hb schlegel, ge scuseria, ma robb, jr cheeseman, g. Scalmani, v. Barone, b. Mennucci, ga petersson et al., gaussian. Inc Wallingford CT 121:150–166

    Google Scholar 

  20. Chem 3D pro 12.0 (Copyright) 1986 to 2009 by CambridgeSoft Corp. [Cambridge, Mass., U.S.A.]

  21. Castellví A, Crespo I, Crosas E, Cámara-Artigas A, Gavira JA, Aranda MA, Parés X, Farrés J, Juanhuix J (2019) Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation. Sci Rep 9(1):3177

    Article  PubMed  PubMed Central  Google Scholar 

  22. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Khan SU, Ahemad N, Chuah LH, Naidu R and Htar TT (2020) Illustrated step by step protocol to perform molecular docking: human estrogen receptor complex with 4-hydroxytamoxifen as a case study. Progress Drug Discovery Biomed Sci 3(1):a0000054–a0000081

  24. Visualizer DS (2005) Accelrys software Inc. Discovery Studio Visualizer

  25. Wang Z, Sun H, Yao X, Li D, Xu L, Li Y, Tian S, Hou T (2016) Comprehensive evaluation of ten docking programs on a diverse set of protein–ligand complexes: the prediction accuracy of sampling power and scoring power. Phys Chem Chem Phys 18(18):12964–12975

    Article  CAS  PubMed  Google Scholar 

  26. Channar PA, Aziz M, Ejaz SA, Chaudhry GES, Saeed A, Ujan R, Hasan A, Ejaz SR, Saeed A (2023) Structural and functional insight into thiazolidinone derivatives as novel candidates for anticancer drug design: in vitro biological and in-silico strategies. J Biomol Struct Dyn 41(3):942–953

    Article  CAS  PubMed  Google Scholar 

  27. Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD and Salmon JK (2006) November. Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing. pp 84-es

  28. Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD (2015) Molecular docking and structure-based drug design strategies. Molecules 20(7):13384–13421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Aziz M, Ejaz SA, Rehman HM, Alsubaie AS, Mahmoud KH, Siddique F, Al-Buriahi MS, Alrowaili ZA (2023) Identification of NEK7 inhibitors: structure based virtual screening, molecular docking, density functional theory calculations and molecular dynamics simulations. J Biomol Struct Dyn 41(14):6894–6908

    Article  CAS  PubMed  Google Scholar 

  30. Aziz M, Ejaz SA, Tamam N, Siddique F, Riaz N, Qais FA, Chtita S, Iqbal J (2022) Identification of potent inhibitors of NEK7 protein using a comprehensive computational approach. Sci Rep 12(1):6404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ejaz SA, Alsfouk AA, Batiha GES, Aborode AT, Ejaz SR, Umar HI, Aziz M, Saeed A, Mahmood HMK, Fayyaz A (2023) Identification of N-(4-acetyl-4, 5-dihydro-5-(7, 8, 9-substituted-tetrazolo [1, 5-a]-quinolin-4-yl)-1, 3, 4-thiadiazol-2-yl) acetamide derivatives as potential caspase-3 inhibitors via detailed computational investigations. Struct Chem 34(2):425–438

    Article  CAS  Google Scholar 

Download references

Funding

The research conducted in this study was financially supported by Princess Nourah bint Abdulrahman University through Project Number PNURSP2023R142, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The funding agency significantly contributed to several aspects of the investigation, including study design, procurement, sample characterization, data processing, interpretation, and paper preparation. The authors are grateful and acknowledge the Simulations Plus, Inc., Lancaster, California for providing the software to Al Ain University, United Arab Emirates to predict ADMET and PK properties.

Author information

Authors and Affiliations

  1. College of Pharmacy, Al Ain University, Al Ain Campus, 64141, Al Ain, United Arab Emirates

    Muhammad Sarfraz & Mosab Arafat

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan

    Mubashir Aziz, Aftab Ahmed & Syeda Abida Ejaz

  3. Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan

    Saira Afzal

  4. Department of Basic Sciences, Mathematics and Humanities, Dawood University of Engineering and Technology, Karachi, 74800, Pakistan

    Pervaiz Ali Channar & Ghulam Abbas Kandhro

  5. Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O Box 84428, 11671, Riyadh, Saudi Arabia

    Bshra A. Alsfouk & Ahlam Sultan

  6. Bahawalpur College of Pharmacy, Bahawalpur Medical and Dental College, Bahawalpur, Pakistan

    Sidra Hassan

  7. Faculty of Pharmacy, Grand Asian University, Sialkot, 51310, Punjab, Pakistan

    Asad Hamad

  8. College of Pharmacy, University of Sargodha, Sargodha, Punjab, Pakistan

    Muhammad Naeem Qaiser

  9. Department of Chemistry and Biochemistry, Texas Tech Universit, Lubboc, TX, 79409–1061, USA

    Farhan Siddique

  10. Department of Pharmaceutical Chemistry, Faculty of Pharmac, Bahauddian Zakariya University, Multan, 60800, Pakistan

    Farhan Siddique

Authors
  1. Muhammad Sarfraz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mubashir Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saira Afzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pervaiz Ali Channar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bshra A. Alsfouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ghulam Abbas Kandhro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sidra Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ahlam Sultan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Asad Hamad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mosab Arafat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Muhammad Naeem Qaiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Aftab Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Farhan Siddique
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Syeda Abida Ejaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MS: methodology, investigations. MA: methodology, experimental material design, Investigations. SA: methodology, investigations. PAC: methodology, experimental material design, investigations. BAA: funding, characterization, resources, validation, visualization, writing—original draft. GAK: investigations, writing—review and editing. SH: methodology, formal analysis. AS: funding, characterization, resources, validation, visualization, writing-original draft. AH: investigation, writing—review and editing. MA (Mosab Arafat): investigation, writing—review and editing. MNQ: methodology, formal analysis. AA: methodology, experimental material design, investigations. FS: methodology, experimental material design, investigations. SAE: conceptualization, methodology, supervision, investigation, writing—review and editing.

Corresponding author

Correspondence to Syeda Abida Ejaz.

Ethics declarations

Competing interests

The authors declare no competing interests.

Conflict of Interest

There is no any financial or personal competing interest among authors.

Ethical Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

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 1852 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

Sarfraz, M., Aziz, M., Afzal, S. et al. Repurposing of Strychnine as the Potential Inhibitors of Aldo–keto Reductase Family 1 Members B1 and B10: Computational Modeling and Pharmacokinetic Analysis. Protein J (2023). https://doi.org/10.1007/s10930-023-10163-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10930-023-10163-z

Keywords

Search

Navigation