Discovery of Repurposable Drugs in the Combination Therapy of Breast Cancer: A Virtual Drug Screening Study

Year 2024, Volume: 8 Issue: 1, 40 - 53, 15.01.2024

Ebru Kırmızıay Rümeysa Demir Ceren Öğütçü Hüseyin Saygın Portakal

https://doi.org/10.33435/tcandtc.1249159

Abstract

Cathepsin D (Cat D) is a lysosomal aspartic acid protease encoded by CTSD gene and has significant biological roles such as degradation of extracellular and intracellular proteins, regulation of apoptosis, hormone processing, antigen processing etc. Furthermore, it is overexpressed by breast cancer cells and it acts a role in many processes affecting the cancer prognosis such as metastasis, angiogenesis, invasion, and drug resistance through regulation of the metabolic pathways and digesting the extracellular matrix (ECM) proteins. Due to that there is no drug targeting Cat D in clinical trial phases, a virtual drug screening in order to reveal possible drugs with high Cat D inhibitory activity from a library composed of 12,111 ligands is carried out with this study. Results have demonstrated that ZINC000003922429 (Adozelesin), ZINC000012358610 (Phthalocyanine), ZINC000051951669 (Bemcentinib), ZINC000003786250 (YM022), and ZINC000150338819 (Ledipasvir) have high binding affinity to Cat D. Among these chemical ligands, YM022 from Drugs in Clinical Trials dataset has been evaluated as most promising one that might be repurposed in the treatment of breast cancer due to its high affinity, convenient ADME and Toxicity properties, and highest bioactivity profiles. However, the possible activity of YM022 should be analyzed with further molecular dynamics (MD) simulations, in vitro and in vivo studies.

Keywords

Breast Cancer, Cathepsin D, Cathepsin Inhibitors, Protease Inhibitors, Virtual Drug Screening, Drug Repurposing

Supporting Institution

There is no supporting institution

Project Number

There is no supporting project

Thanks

There is no acknowledgement

References

• [1] M. Leary, S. Heerboth, K. Lapinska, and S. Sarkar, Sensitization of drug resistant cancer cells: A matter of combination therapy, Cancers 10 (2018) 1–18.
• [2] T. Oskarsson, Extracellular matrix components in breast cancer progression and metastasis, Breast 22 (2013) 66–S72.
• [3] B. Yue, Biology of the extracellular matrix: An overview, J. Glaucoma 23 (2014) 20–23.
• [4] E. Di Cera, Serine proteases, IUBMB Life 61 (2009) 510–515.
• [5] S. Verma, R. Dixit, and K. C. Pandey, Cysteine proteases: Modes of activation and future prospects as pharmacological targets, Front. Pharmacol. 7 (2016) 1–12.
• [6] J. Tang, R. N. S. Wong, Evolution in the structure and function of aspartic proteases, J. Cell. Biochem. 33 (1987) 53–63.
• [7] P. Benes, V. Vetvicka, and M. Fusek, Cathepsin D-Many functions of one aspartic protease, Crit. Rev. Oncol. Hematol. 68 (2008) 12–28.
• [8] E. T. Baldwin et al., Crystal structures of native and inhibited forms of human cathepsin D: Implications for lysosomal targeting and drug design, Proc. Natl. Acad. Sci. U. S. A. 90 (1993) 6796–6800.
• [9] T. Houben et al., Cathepsin D regulates lipid metabolism in murine steatohepatitis, Sci. Rep. 7 (2017) 1–10.
• [10] P. Gan et al., Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation-mediated neurotoxicity through inhibition of NF-κB signalling pathway in Parkinson’s disease model, Clin. Exp. Pharmacol. Physiol. 46 (2019) 337–349.
• [11] J. Liu, L. Yang, H. Tian, and Q. Ma, Cathepsin D is involved in the oxygen and glucose deprivation/reperfusion-induced apoptosis of astrocytes, Int. J. Mol. Med. 38 (2016) 1257–1263.
• [12] A. Eguchi, A. E. Feldstein, Lysosomal Cathepsin D contributes to cell death during adipocyte hypertrophy, Adipocyte 2 (2013) 170–175.
• [13] N. Zaidi, A. Maurer, S. Nieke, and H. Kalbacher, Cathepsin D: A cellular roadmap, Biochem. Biophys. Res. Commun. 376 (2008) 5–9.
• [14] C. E. Chwieralski, T. Welte, and F. Bühling, Cathepsin-regulated apoptosis, Apoptosis 11 (2006) 143–149.
• [15] S. A. Abideen, M. Khan, M. Irfan, and S. Ahmad, Deciphering the dynamics of cathepsin D as a potential drug target to enhance anticancer drug-induced apoptosis, J. Mol. Liq. 361 (2022) 119677.
• [16] A. A. Aghdassi et al., Cathepsin d regulates cathepsin b activation and disease severity predominantly in inflammatory cells during experimental pancreatitis, J. Biol. Chem. 293 (2018) 1018–1029.
• [17] A. Amritraj, Y. Wang, T. J. Revett, D. Vergote, D. Westaway, and S. Kar, Role of Cathepsin d in u18666a-induced neuronal cell death potential implication in Niemann-Pick type c disease pathogenesis, J. Biol. Chem. 288 (2013) 3136–3152.
• [18] E. Liaudet-Coopman et al., Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis, Cancer Lett. 237 (2006) 167–179.
• [19] C. Zhang, M. Zhang, and S. Song, Cathepsin D enhances breast cancer invasion and metastasis through promoting hepsin ubiquitin-proteasome degradation, Cancer Lett. 438 (2018) 105–115.
• [20] L. B. Alcaraz et al., A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment, Theranostics 11 (2021) 6173–6192.
• [21] H. S. Anantaraju, M. B. Battu, S. Viswanadha, D. Sriram, and P. Yogeeswari, Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers, Mol. Divers. 20 (2016) 521–535.
• [22] D. E. Abbott et al., Reevaluating cathepsin D as a biomarker for breast cancer: Serum activity levels versus histopathology, Cancer Biol. Ther. 9 (2010) 23–30.
• [23] N. Bidère et al., Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis, J. Biol. Chem. 278 (2003) 31401–31411.
• [24] R. Houštecká et al., Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis, J. Med. Chem. 63 (2020) 1576–1596.
• [25] A. Gimeno et al., The light and dark sides of virtual screening: What is there to know?, Int. J. Mol. Sci. 20 (2019) 1375.
• [26] E. F. Pettersen et al., UCSF Chimera - A visualization system for exploratory research and analysis, J. Comput. Chem. 25 (2004) 1605–1612.
• [27] S. Dallakyan, A. Olson, Small-Molecule Library Screening by Docking with PyRx, NY: Springer New York, U.S.A, 2015, 243-250.
• [28] O. Trott, A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, J. Comput. Chem. 17 (2011) 295-304.
• [29] C. Dominguez, R. Boelens, and A. M. J. J. Bonvin, HADDOCK: A protein-protein docking approach based on biochemical or biophysical information, J. Am. Chem. Soc. 125 (2003) 1731–1737.
• [30] A. Porollo, J. Meller, Prediction-Based Fingerprints of Protein-Protein Interactions, Proteins 66 (2007) 630-645.
• [31] https://www.organic-chemistry.org/prog/peo/, January 2017, Accessed: 06.12.2022.
• [32] A. Daina, O. Michielin, and V. Zoete, SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep. 7 (2017) 1–13.
• [33] https://www.molinspiration.com, January 1986, Accessed: 07.12.2022.
• [34] S. J. Kim, K. H. Kim, E. R. Ahn, B. C. Yoo, and S. Y. Kim, Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival, Amino Acids 44 (2013) 73–80.
• [35] U. Grädler et al., Structure-based optimization of non-peptidic Cathepsin D inhibitors, Bioorganic Med. Chem. Lett. 24 (2014) 4141–4150.
• [36] M. K. Azim, W. Ahmed, I. A. Khan, N. A. Rao, and K. M. Khan, Identification of acridinyl hydrazides as potent aspartic protease inhibitors, Bioorganic Med. Chem. Lett. 18 (2008) 3011–3015.
• [37] Z. S. Saify et al., New benzimidazole derivatives as antiplasmodial agents and plasmepsin inhibitors: Synthesis and analysis of structure-activity relationships, Bioorganic Med. Chem. Lett. 22 (2012) 1282–1286.
• [38] W. Ahmed, U. Jabeen, and S. Khaliq, New inhibitors of proteolytic enzymes Cathepsin D and Plasmepsin II, Pakistan J. Biochem. Mol. Biol. 47 (2014) 129–132.
• [39] L. Gangoda et al., Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin, Oncotarget 6 (2015) 11175–11190.
• [40] W. Ahmed, I. A. Khan, M. N. Arshad, W. A. Siddiqui, M. A. Haleem, and M. K. Azim, Identification of Sulfamoylbenzamide derivatives as selective cathepsin D inhibitors, Pak. J. Pharm. Sci. 26 (2013) 687–690.
• [41] S. R. M. Ibrahim et al., Thiophenes—Naturally Occurring Plant Metabolites: Biological Activities and In Silico Evaluation of Their Potential as Cathepsin D Inhibitors, Plants 11 (2022) 1-64.
• [42] P. R. Cao, M. M. McHugh, T. Melendy, and T. Beerman, The DNA minor groove-alkylating cyclopropylpyrroloindole drugs adozelesin and bizelesin induce different DNA damage response pathways in human colon carcinoma HCT116 cells, Mol. Cancer Ther. 2 (2003) 651–659.
• [43] B. K. Bhuyan, K. S. Smith, E. G. Adams, T. L. Wallace, D. D. Von Hoff, and L. H. Li, Adozelesin, a potent new alkylating agent: cell-killing kinetics and cell-cycle effects, Cancer Chemother. Pharmacol. 30 (1992) 348–354.
• [44] T. Furuyama, K. Satoh, T. Kushiya, and N. Kobayashi, Design, synthesis, and properties of phthalocyanine complexes with main-group elements showing main absorption and fluorescence beyond 1000 nm, J. Am. Chem. Soc. 136 (2014) 765–776.
• [45] C. C. Rennie, R. M. Edkins, Targeted cancer phototherapy using phthalocyanine-anticancer drug conjugates, Dalt. Trans. 51 (2022) 13157–13175.
• [46] A. Hoel et al., Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model, J. Cell. Mol. Med. 25 (2021) 7407–7417.
• [47] A. Garcia-Sampedro, G. Gaggia, A. Ney, I. Mahamed, and P. Acedo, The state-of-the-art of phase ii/iii clinical trials for targeted pancreatic cancer therapies, J. Clin. Med. 10 (2021) 1–45.
• [48] D. Zdzalik-Bielecka, K. Kozik, A. Po’swiata, K. Jastrzębski, M. Jakubik, and M. Miaczyńska, Bemcentinib and Gilteritinib Inhibit Cell Growth and Impair the Endo-Lysosomal and Autophagy Systems in an AXL-Independent Manner, Mol. Cancer Res. 20 (2022) 446–455.
• [49] H. Yuki et al., YM022, a potent and selective gastrin/CCK-B receptor antagonist, inhibits peptone meal-induced gastric acid secretion in Heidenhain pouch dogs, Dig. Dis. Sci. 42 (1997) 707–714.
• [50] S. Attoub, L. Moizo, J. P. Laigneau, B. Alchepo, M. J. M. Lewin, and A. Bado, YM022, a highly potent and selective CCK(B) antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands, Fundam. Clin. Pharmacol. 12 (1998) 256–262.
• [51] M. Charlton et al., Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease, Gastroenterology 149 (2015) 649–659.
• [52] C. C. Lo et al., Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4–6 infection: Real-world evidence from a nationwide registry in Taiwan, J. Formos. Med. Assoc. 121 (2022) 1567–1578.
• [53] M. Arshad, M. S. Khan, S. A. A. Nami, S. I. Ahmad, M. Kashif, and A. Anjum, Synthesis, characterization, biological, and molecular docking assessment of bioactive 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl) moieties, J. Iran. Chem. Soc. 18 (2021) 1713–1727.