Skip to main content
SpringerLink
Log in

Binding mechanism of selective cathepsin K/S inhibition revealed from molecular simulations

  • Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

Cathepsin K and S are two isoforms of cysteine protease with diverse biological functions in the aspect of osteoporosis and autoimmune diseases. Accordingly, the homologous sequence and similar binding site features among CTSK/S may lead to unselective inhibition and side effects. To address such issue, various computational strategies were applied in the current study to explore the selectivity mechanism of CTSK/S inhibitors, including sequence alignment, molecular docking, MD simulations, MM/GBSA energy calculation, and so on. Our findings highlight the notable effects of CTSK residues Glu59 and Tyr67, as well as CTSS residue Asn67, on inhibition selectivity. Overall, this study provides an informative guideline for the rational design of CTSK/S selective 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
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

Similar content being viewed by others

Data availability

Not applicable.

Materials availability

Not applicable.

References

  1. Hook V, Yoon M, Mosier C, Ito G, Podvin S, Head BP et al (2020) Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders. Biochim Biophys Acta Proteins Proteom 1868(8):140428. https://doi.org/10.1016/j.bbapap.2020.140428

  2. Drake MT, Clarke BL, Oursler MJ, Khosla S (2017) Cathepsin K Inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr Rev 38(4):325–50. https://doi.org/10.1210/er.2015-1114

  3. Sophia Thanei, Michel Theron, Ana Patricia Silva, Bernhard Reis, Branco L, Lucia Schirmbeck et al (2017) Cathepsin S inhibition suppresses autoimmune-triggered inflammatory responses in macrophages. Biochem Pharmacol 146:151–64. https://doi.org/10.1016/j.bcp.2017.10.001

  4. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B et al (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta 1824(1):68–88. https://doi.org/10.1016/j.bbapap.2011.10.002

  5. Xiao-Yu Yuan, Ding-Yi Fu, Xing-Feng Ren, Xuexun Fang, Lincong Wang, Zouc S et al (2013) Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling. Org Biomol Chem 11(35):5847–52. https://doi.org/10.1039/c3ob41165f

  6. Robichaud J, Bayly C, Oballa R, Prasit P, Mellon C, Falgueyret JP et al (2014) Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors. Bioorg Med Chem Lett 14(16):4291–5 https://doi.org/10.1016/j.bmcl.2004.05.087

  7. Ahmad S, Siddiqi MI (2017) Insights from molecular modeling into the selective inhibition of cathepsin S by its inhibitor. J Mol Model 23(3):92. https://doi.org/10.1007/s00894-017-3255-6

  8. Lu J, Wang M, Wang Z, Fu Z, Lu A, Zhang G (2018) Advances in the discovery of cathepsin K inhibitors on bone resorption. J Enzyme Inhib Med Chem 33(1):890–904. https://doi.org/10.1080/14756366.2018.1465417

  9. Mukherjee K, Chattopadhyay N (2016) Pharmacological inhibition of cathepsin K: a promising novel approach for postmenopausal osteoporosis therapy. Biochem Pharmacol 117:10–9. https://doi.org/10.1016/j.bcp.2016.04.010

  10. Novinec M, Lenarcic B (2013) Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem 394(9):1163–79. https://doi.org/10.1515/hsz-2013-0134

  11. Yamashitaa DS, Dodds RA (2000) Cathepsin K and the design of inhibitors of cathepsin K. Curr Pharm Des 6(1):1–24. https://doi.org/10.2174/1381612003401569

  12. Yasuda Y, Kaleta J, Bromme D (2005) The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 57(7):973–93. https://doi.org/10.1016/j.addr.2004.12.013

  13. Saegusa K, Ishimaru N, Yanagi K, Arakaki R, Ogawa K, Saito I, et al. Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J Clin Investig 110(3):361–9. https://doi.org/10.1172/jci200214682

  14. Small DM, Brown RR, Doherty DF, Abladey A, Zhou-Suckow Z, Delaney RJ et al (2019) Targeting of cathepsin S reduces cystic fibrosis-like lung disease. Eur Respir J 53(3):1801523. https://doi.org/10.1183/13993003.01523-2018

  15. Dheilly E, Battistello E, Katanayeva N, Sungalee S, Michaux J, Duns G et al (2020) Cathepsin S regulates antigen processing and T cell activity in non-Hodgkin lymphoma. Cancer Cell 37(5):674–89 e12. https://doi.org/10.1016/j.ccell.2020.03.016

  16. Costantino CM, Ploegh HL, Hafler DA (2009) Processing in human CD4 + HLA-DR+ T cathepsin S regulates class II MHC cells. J Immunol 183(2):945–52. https://doi.org/10.4049/jimmunol.0900921

  17. Beers C, Burich A, Kleijmeer MJ, Griffith JM, Wong P, Rudensky AY (2005) Cathepsin S controls MHC class II-mediated antigen presentation by epithelial cells in vivo. J Immunol 174(3):1205–12. https://doi.org/10.4049/jimmunol.174.3.1205

  18. Chatterjee AK, Liu H, Tully DC, Guo J, Epple R, Russo R et al (2007) Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S. Bioorg Med Chem Lett 17(10):2899–903. https://doi.org/10.1016/j.bmcl.2007.02.049

  19. Kaori Kubo, Yuka Kawato, Koji Nakamura, Yutaka Nakajima, Terry Y Nakagawa, Kaori Hanaoka et al (2018) Effective suppression of donor specific antibody production by cathepsin S inhibitors in a mouse transplantation model. European J Pharmacol 838:145–52. https://doi.org/10.1016/j.ejphar.2018.09.007

  20. McClung MR, O'Donoghue ML, Papapoulos SE, Bone H, Langdahl B, Saag KG et al (2019) Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study. Lancet Diabetes Endocrinol 7(12):899–911. https://doi.org/10.1016/s2213-8587(19)30346-8

  21. Palmer JT, Bryant C, Wang D-X, Davis DE, Setti EL, Rydzewski RM et al (2005) Design and synthesis of Tri-Ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K. J Med Chem 48(24):7520–34. https://doi.org/10.1021/jm058198r

  22. Yoo Y, Choi E, Kim Y, Cha Y, Um E, Kim Y et al (2022) Therapeutic potential of targeting cathepsin S in pulmonary fibrosis. Biomed Pharmacother 145:112245. https://doi.org/10.1016/j.biopha.2021.112245

  23. Stumpfe D, Sisay MT, Frizler M, Vogt I, Gutschow M, Bajorath J (2010) Inhibitors of cathepsins K and S identified using the DynaMAD virtual screening algorithm. Chem Med Chem 5(1):61–4. https://doi.org/10.1002/cmdc.200900457

  24. Wang H, Wang Y, Li C, Wang H, Geng X, Hu B et al (2021)Structural basis for tailor-made selective PI3K α/β inhibitors: a computational perspective. New J Chem 45(1):373–82. https://doi.org/10.1039/d0nj04216a

  25. Bhachoo J, Beuming T (2017) Investigating protein-peptide interactions using the Schrodinger computational suite. Methods Mol Biol 1561:235–54. https://doi.org/10.1007/978-1-4939-6798-8_14

  26. Roos K, Wu C, Damm W, Reboul M, Stevenson JM, Lu C et al (2019) OPLS3e: extending force field coverage for drug-like small molecules. J Chem Theory Comput 15(3):1863–74. https://doi.org/10.1021/acs.jctc.8b01026

  27. Kasahara K, Fukuda I, Nakamura H(2014) A novel approach of dynamic cross correlation analysis on molecular dynamics simulations and its application to Ets1 dimer-DNA complex. PLoS One 9(11):e112419. https://doi.org/10.1371/journal.pone.0112419

  28. Genheden S, Ryde U (2015) The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 10(5):449–61. https://doi.org/10.1517/17460441.2015.1032936

  29. Luo L, Zhong A, Wang Q, Zheng T (2021) Structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET, and molecular dynamics (MD) simulation of potential inhibitors of PD-L1 from the Library of Marine Natural Products. Mar Drugs 20(1):29. https://doi.org/10.3390/md20010029

Download references

Funding

This work was supported by an award from the Taishan Industry Leading Talents Project (2018TSCYCX-03).

Author information

Author notes

  1. Qinyi Zhong and Jiasi Luan contributed equally to this paper.

Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

    Qinyi Zhong

  2. School of Medical Devices, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

    Jiasi Luan

  3. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

    Baichun Hu

  4. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

    Yan Ma & Fengjiao Zhang

  5. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

    Feng Xu

Authors
  1. Qinyi Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiasi Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baichun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fengjiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Qinyi Zhong and Jiasi Luan wrote the main manuscript text, and Baichun Hu and Yan Ma prepared the data. All authors reviewed the manuscript.

Corresponding author

Correspondence to Fengjiao Zhang.

Ethics declarations

Ethical approval

Not applicable.

Competing interests

The authors declare no competing interests.

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 4071 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

Zhong, Q., Luan, J., Hu, B. et al. Binding mechanism of selective cathepsin K/S inhibition revealed from molecular simulations. Struct Chem 34, 1911–1925 (2023). https://doi.org/10.1007/s11224-023-02136-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-023-02136-w

Keywords

Search

Navigation