AXL inhibitors selected by molecular docking: Option for reducing SARS-CoV-2 entry into cells

Galindo-Hernández, Octavio; Vique-Sánchez, José Luis

doi:10.2478/acph-2022-0024

Abstract

The COVID-19 pandemic is ongoing and the benefit from vaccines is still insufficient since COVID-19 continues to be dia g-nosed in vaccinated individuals. It is, therefore, necessary to propose specific pharmacological treatments against COVID-19. A new therapeutic target on the human cellular membrane is AXL (anexelekto), proposed as an independent pathway by which interaction with the S protein of SARS-CoV-2 allows the virus to enter the cell, without the participation of ACE2. AXL serves as another gate through which SARS-CoV-2 can enter cells. Therefore, any stage of COVID-19 could be ameliorated by hindering the interaction between AXL and SARS-CoV-2. This study proposes ten compounds (1–10), selected by mole-cu lar docking and using a library of nearly 500,000 compounds, to develop a new drug that will decrease the interaction of AXL with the S protein of SARS-CoV-2. These compounds have a specific potential site of interaction with AXL, between Glu59, His61, Glu70 and Ser74 amino acids. This site is necessary for the interaction of AXL with the S protein. With this, we propose to develop a new adjuvant treatment against COVID-19.

References

1. E. Dong, H. Du and L. Gardner, An interactive web-based dashboard to track COVID-19 in real time, Lancet Infect. Dis. 20(5) (2020) 533–534; https://doi.org/10.1016/S1473-3099(20)30120-110.1016/S1473-3099(20)30120-1
Search in Google Scholar Back to article
2. M. Hoffmann, H. Kleine-Weber, S. Schroeder, N. Krüger, T. Herrler, S. Erichsen, T. S. Schiergens, G. Herrler, N.-H. Wu, A. Nitsche, M. A. Müller, C. Drosten and S. Pöhlmann, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, 181(2) Cell (2020) 271–280; https://doi.org/10.1016/j.cell.2020.02.05210.1016/j.cell.2020.02.052
Search in Google Scholar Back to article
3. L. K. Gadanec, K. R. McSweeney, T. Qaradakhi, B. Ali, A. Zulli and V. Apostolopoulos, Can SARSCoV-2 virus use multiple receptors to enter host cells?, Int. J. Mol. Sci. 22(3) (2021) Article ID 992 (36 pages); https://doi.org/10.3390/ijms2203099210.3390/ijms22030992
Search in Google Scholar Back to article
4. C. G. Benítez-Cardoza and J. L. Vique-Sánchez, Potential inhibitors of the interaction between ACE2 and SARS-CoV-2 (RBD), to develop a drug, Life Sci. 256 (2020) Article ID 117970; https://doi.org/10.1016/j.lfs.2020.11797010.1016/j.lfs.2020.117970
Search in Google Scholar Back to article
5. S. M. Kishk, R. M. Kishk, A. S. A. Yassen, M. S. Nafie, N. A. Nemr, G. ElMasry, S. Al-Rejaie and C. Simons, Molecular insights into human transmembrane protease serine-2 (TMPS2) inhibitors against SARS-CoV2: Homology modelling, molecular dynamics, and docking studies, Molecules 25(21) (2020) Article ID 5007 (16 pages); https://doi.org/10.3390/molecules2521500710.3390/molecules25215007
Search in Google Scholar Back to article
6. J. L. Vique-Sánchez, Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking, Bioorg. Med. Chem. 33 (2021) Article ID 116040; https://doi.org/10.1016/j.bmc.2021.11604010.1016/j.bmc.2021.116040
Search in Google Scholar Back to article
7. Y. Choi, B. Shin, K. Kang, S. Park and B. R. Beck, Target-centered drug repurposing predictions of human angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) interacting approved drugs for coronavirus disease 2019 (COVID-19) treatment through a drug-target interaction deep learning model, Viruses 12(11) (2020) Article ID 1325 (11 pages); https://doi.org/10.3390/v12111325
Search in Google Scholar Back to article
8. S. Wang, Z. Qiu, Y. Hou, X. Deng, W. Xu, T. Zheng, P. Wu, S. Xie, W. Bian, C. Zhang, Z. Sun, K. Liu, C. Shan, A. Lin, S. Jiang, Y. Xie, Q. Zhou, Lu Lu, J. Huang and Xu Li, AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells, Cell Res. 31 (2021) 126–140; https://doi.org/10.1038/s41422-020-00460-y10.1038/s41422-020-00460-y
Search in Google Scholar Back to article
9. C. Xu, A. Wang, Ke Geng, W. Honnen, X. Wang, N. Bruiners, S. Singh, F. Ferrara, S. D’Angelo, A. R. M. Bradbury, M. L. Gennaro, D. Liu, A. Pinter and T. L. Chang, Human immunodeficiency viruses pseudotyped with SARS-CoV-2 spike proteins infect a broad spectrum of human cell lines through multiple entry mechanisms, Viruses 13(6) (2021) Article ID 953 (17 pages); https://doi.org/10.3390/v1306095310.3390/v13060953
Search in Google Scholar Back to article
10. C. Lai and G. Lemke, An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system, Neuron 6 (1991) 691–704; https://doi.org/10.1016/0896-6273(91)90167-X10.1016/0896-6273(91)90167-X
Search in Google Scholar Back to article
11. Y. Tian, Z. Zhang, L. Miao, Z. Yang, J. Yang, Y. Wang, D. Qian, H. Cai and Y. Wang, Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells, Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 24 (2016) 295–303; https://doi.org/10.3727/09650401614648701447814
Search in Google Scholar Back to article
12. T. Pillaiyar and S. Laufer, Kinases as potential therapeutic targets for anti-coronaviral therapy, J. Med. Chem. (2021) in press; https://doi.org/10.1021/acs.jmedchem.1c0033510.1021/acs.jmedchem.1c00335818904434081439
Search in Google Scholar Back to article
13. J. Huckriede, S. B. Anderberg, A. Morales, F. de Vries, M. Hultström, A. Bergqvist, J. T. Ortiz-Pérez, J. W. Sels, K. Wichapong, M. Lipcsey, M. van de Poll, A. Larsson, T. Luther, C. Reutelingsperger, P. G. de Frutos, R. Frithiof and G. A. F. Nicolaes, Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients, Sci. Rep. 11 (2021) Article ID 15701 (12 pages); https://doi.org/10.1038/s41598-021-95209-x10.1038/s41598-021-95209-x833332134344929
Search in Google Scholar Back to article
14. J. Dai, X. Teng, S. Jin and Y. Wu, The antiviral roles of hydrogen sulfide by blocking the interaction between SARS-CoV-2 and its potential cell surface receptors, Oxid. Med. Cell. Longev. 2021 (2021) Article ID 7866992 (11 pages); https://doi.org/10.1155/2021/786699210.1155/2021/7866992842116134497683
Search in Google Scholar Back to article
15. M. S. Kariolis, Y. R. Miao, A. Diep, S. E. Nash, M. M. Olcina, D. Jiang, D. S. Jones II, S. Kapur, I. I. Mathews, A. C. Koong, E. B. Rankin, J. R. Cochran and A. J. Giaccia, Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies, J. Clin. Invest. 127(1) (2016) 183–198; https://doi.org/10.1172/JCI8561010.1172/JCI85610519971627893463
Search in Google Scholar Back to article
16. S. H. Chung, J. Park, J. W. Lee, J. Song, D. Jung and K. H. Min, Structure-activity relationship of 7-aryl-2-anilino-pyrrolopyrimidines as Mer and Axl tyrosine kinase inhibitors, J. Enzyme Inhib. Med. Chem. 35(1) (2020) 1822–1833; https://doi.org/10.1080/14756366.2020.182540710.1080/14756366.2020.1825407753438332972253
Search in Google Scholar Back to article
17. M. L. Lotsberg, K. Wnuk-Lipinska, S. Terry, T. Z. Tan, N. Lu, L. Trachsel-Moncho, G. V. Røsland, M. I. Siraji, M. Hellesøy, A. Rayford, K. Jacobsen, H. J. Ditzel, O. K. Vintermyr, T. G. Bivona, J. Minna, R. A. Brekken, B. Baguley, D. Micklem, L. A. Akslen, G. Gausdal, A. Simonsen, J. P. Thiery, S. Chouaib, J. B. Lorens and A. S. Tenfjord Engelsen, AXL targeting abrogates autophagic flux and induces immunogenic cell death in drug-resistant cancer cells, J. Thorac. Oncol. 15(6) (2020) 973–999; https://doi.org/10.1016/j.jtho.2020.01.01510.1016/j.jtho.2020.01.015739755932018052
Search in Google Scholar Back to article
18. A. Tutusaus, M. Marí, J. T. Ortiz-Pérez, G. A. F. Nicolaes, A. Morales and P. García de Frutos, Role of vitamin K-dependent factors protein S and GAS6 and TAM receptors in SARS-CoV-2 infection and COVID-19-associated immunothrombosis, Cells 9(10) (2020) ID 2186 (15 pages); https://doi.org/10.3390/cells910218610.3390/cells9102186760176232998369
Search in Google Scholar Back to article
19. S. N. Batchu, J. Xia, K. A. Ko, M. M. Doyley, J.-I. Abe, C. N. Morrell and V. A. Korshunov, Axl modulates immune activation of smooth muscle cells in vein graft remodeling, Am. J. Physiol. Circ. Physiol. 309(6) (2015) H1048–H1058; https://doi.org/10.1152/ajpheart.00495.201510.1152/ajpheart.00495.2015459136026276821
Search in Google Scholar Back to article
20. M. Tanaka and D. W. Siemann, Axl signaling is an important mediator of tumor angiogenesis, Oncotarget 10(30) (2019) 2887–2898; https://doi.org/10.18632/oncotarget.2688210.18632/oncotarget.26882649959731080559
Search in Google Scholar Back to article
21. C. A. Stewart, C. M. Gay, K. Ramkumar, K. R. Cargill, R. J. Cardnell, M. B. Nilsson, S. Heeke, E. M. Park, S. T. Kundu, L. Diao, Q. Wang, L. Shen, Y. Xi, B. Zhang, C. M. Della Corte, Y. Fan, K. Kundu, B. Gao, K. Avila, C. R. Pickering, F. M. Johnson, J. Zhang, H. Kadara, J. D. Minna, D. L. Gibbons, J. Wang, J. V. Heymach and L. Averett Byers, Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology, bioRxiv preprint posted January 28, 2021; https://doi.org/10.1101/2020.05.28.12229110.1101/2020.05.28.122291730220632577652
Search in Google Scholar Back to article
22. M. Bouhaddou, D. Memon, B. Meyer, K. M. White, V. V. Rezelj, M. Correa Marrero, B. J. Polacco, J. E. Melnyk, S. Ulferts, R. M. Kaake, J. Batra, A. L. Richards, E. Stevenson, D. E. Gordon, A. Rojc, K. Obernier, J. M. Fabius, M. Soucheray, L. Miorin, E. Moreno, C. Koh, Q. D. Tran, A. Hardy, R. Robinot, T. Vallet, B. E. Nilsson-Payant, C. Hernandez-Armenta, A. Dunham, S. Weigang, J. Knerr, M. Modak, D. Quintero, Y. Zhou, A. Dugourd, A. Valdeolivas, T. Patil, Q. Li, R. Hüttenhain, M. Cakir, M. Muralidharan, M. Kim, G. Jang, B. Tutuncuoglu, J. Hiatt, J. Z. Guo, J. Xu, S. Bouhaddou, C. J. P. Mathy, A. Gaulton, E. J. Manners, E. Félix, Y. Shi, M. Goff, J. K. Lim, T. McBride, M. C. O’Neal, Y. Cai, J. C. J. Chang, D. J. Broadhurst, S. Klippsten, E. De Wit, A. R. Leach, T. Kortemme, B. Shoichet, M. Ott, J. Saez-Rodriguez, B. R. tenOever, R. D. Mullins, E. R. Fischer, G. Kochs, R. Grosse, A. García-Sastre, M. Vignuzzi, J. R. Johnson, K. M. Shokat, D. L. Swaney, P. Beltrao and N. J. Krogan, The global phosphorylation landscape of SARS-CoV-2 infection, Cell 182(3) (2020) 685–712; https://doi.org/10.1016/j.cell.2020.06.03410.1016/j.cell.2020.06.034732103632645325
Search in Google Scholar Back to article
23. C. G. Benítez-Cardoza, L. G. Brieba, R. Arroyo, A. Rojo-Domínguez and J. L. Vique-Sánchez, Triose-phosphate isomerase as a therapeutic target against trichomoniasis, Mol. Biochem. Parasitol. 246 (2021) Article ID 111413; https://doi.org/10.1016/j.molbiopara.2021.11141310.1016/j.molbiopara.2021.111413
Search in Google Scholar Back to article
24. ChemBridge Corp., EXPRESS-Pick Stock, https://chembridge.com/screening_libraries/#EXPRESSPick; last acces date November 10, 2020
Search in Google Scholar Back to article
25. C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev. 23(1–3) (1997) 3–25; https://doi.org/10.1016/S0169-409X(96)00423-110.1016/S0169-409X(96)00423-1
Search in Google Scholar Back to article
26. Advanced Chemistry Development, Inc., PhysChem, ADME & Toxicity, Version 2021.1.1, Toronto (ON, Canada) 2021; www.acdlabs.com; last access date September 15, 2021
Search in Google Scholar Back to article
27. J. Dong, N.-N. Wang, Z.-J. Yao, L. Zhang, Y. Cheng, D. Ouyang, A.-P. Lu and D.-S. Cao, ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database, J. Cheminform. 10 (2018) Article ID 29 (11 pages); https://doi.org/10.1186/s13321-018-0283-x10.1186/s13321-018-0283-x602009429943074
Search in Google Scholar Back to article
28. P. Banerjee, A. O. Eckert, A. K. Schrey and R. Preissner, ProTox-II: a webserver for the prediction of toxicity of chemicals, Nucleic Acids Res. 46(W1) (2018) W257–W263; https://doi.org/10.1093/nar/gky31810.1093/nar/gky318603101129718510
Search in Google Scholar Back to article
29. X. Chi, R. Yan, J. Zhang, G. Zhang, Y. Zhang, M. Hao, Z. Zhang, P. Fan, Y. Dong, Y. Yang, Z. Chen, Y. Guo, J. Zhang, Y. Li, X. Song, Y. Chen, L. Xia, L. Fu, L. Hou, J. Xu, C. Yu, J. Li, Q. Zhou and W. Chen, A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2, Science 369(6504) (2020) 650–655; https://doi.org/10.1126/science.abc695210.1126/science.abc6952731927332571838
Search in Google Scholar Back to article
30. C. V. Rothlin, E. A. Carrera-Silva, L. Bosurgi and S. Ghosh, TAM receptor signaling in immune homeostasis, Annu. Rev. Immunol. 33 (2015) 355–391; https://doi.org/10.1146/annurev-immunol-032414-11210310.1146/annurev-immunol-032414-112103449191825594431
Search in Google Scholar Back to article

AXL inhibitors selected by molecular docking: Option for reducing SARS-CoV-2 entry into cells

Abstract

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