In silico drug screen reveals potential competitive MTHFR inhibitors for clinical repurposing

References

• Abraham, M. J., Murtola, T., Schulz, R., Páll, S., Smith, J. C., Hess, B., & Lindah, E. (2015). Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1-2, 19–25. https://doi.org/10.1016/j.softx.2015.06.001
   Google Scholar
• Aier, I., Varadwaj, P. K., & Raj, U. (2016). Structural insights into conformational stability of both wild-type and mutant EZH2 receptor. Scientific Reports, 6, 34984. https://doi.org/10.1038/srep34984
   PubMed Web of Science ®Google Scholar
• Al-Sha’er, M. A., Basheer, H. A., & Taha, M. O. (2022). Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores. Molecular Diversity, https://doi.org/10.1007/s11030-022-10434-4
   PubMed Web of Science ®Google Scholar
• Arnittali, M., Rissanou, A. N., & Harmandaris, V. (2019). Structure of biomolecules through molecular dynamics simulations. Procedia Computer Science, 156, 69–78. https://doi.org/10.1016/j.procs.2019.08.181
   Google Scholar
• Balbuena-Rebolledo, I., Padilla-Martínez, I. I., Rosales-Hernández, M. C., & Bello, M. (2021). Repurposing FDA drug compounds against breast cancer by targeting egfr/her2. Pharmaceuticals, 14(8), 791. https://doi.org/10.3390/ph14080791
   Web of Science ®Google Scholar
• Benet, L. Z., Hosey, C. M., Ursu, O., & Oprea, T. I. (2016). BDDCS, the Rule of 5 and drugability. In Advanced drug delivery reviews (Vol. 101, pp.89–98). Elsevier B.V. https://doi.org/10.1016/j.addr.2016.05.007
   Google Scholar
• Bezerra, G. A., Holenstein, A., Foster, W. R., Xie, B., Hicks, K. G., Bürer, C., Lutz, S., Mukherjee, A., Sarkar, D., Bhattacharya, D., Rutter, J., Talukdar, A., Brown, P. J., Luo, M., Shi, L., Froese, D. S., & Yue, W. W. (2021). Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain. Biochimie, 183, 100–107. https://doi.org/10.1016/j.biochi.2021.01.007
   PubMed Web of Science ®Google Scholar
• Bhatia, M., Thakur, J., Suyal, S., Oniel, R., Chakraborty, R., Pradhan, S., Sharma, M., Sengupta, S., Laxman, S., Masakapalli, S. K., & Bachhawat, A. K. (2020). Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism. The Journal of Biological Chemistry, 295(47), 16037–16057. https://doi.org/10.1074/jbc.RA120.015129
   PubMed Web of Science ®Google Scholar
• Burda, P., Schäfer, A., Suormala, T., Rummel, T., Bürer, C., Heuberger, D., Frapolli, M., Giunta, C., Sokolová, J., Vlášková, H., Kožich, V., Koch, H. G., Fowler, B., Froese, D. S., & Baumgartner, M. R. (2015). Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: Molecular genetic and enzymatic characterization of 76 patients. Human Mutation, 36(6), 611–621. https://doi.org/10.1002/humu.22779
   PubMed Web of Science ®Google Scholar
• Chakraborty, C., Sharma, A. R., Bhattacharya, M., Agoramoorthy, G., & Lee, S. S. (2021). The drug repurposing for COVID-19 clinical trials provide very effective therapeutic combinations: Lessons learned from major clinical studies. Frontiers in Pharmacology, 12, 704205. https://doi.org/10.3389/fphar.2021.704205
   PubMed Web of Science ®Google Scholar
• Chen, D., Oezguen, N., Urvil, P., Ferguson, C., Dann, S. M., & Savidge, T. C. (2016). Regulation of protein-ligand binding affinity by hydrogen bond pairing. Science Advances, 2(3), 433-443. https://doi.org/10.1126/sciadv.1501240
   Web of Science ®Google Scholar
• Chen, Z., Karaplis, A. C., Ackerman, S. L., Pogribny, I. P., Melnyk, S., Lussier-Cacan, S., Chen, M. F., Pai, A., John, S. W. M., Smith, R. S., Bottiglieri, T., Bagley, P., Selhub, J., Rudnicki, M. A., James, S. J., & Rozen, R. (2001). Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Human Molecular Genetics, 10(5), 433–443. https://doi.org/10.1093/hmg/10.5.433
   PubMed Web of Science ®Google Scholar
• Chen, J., Gammon, M. D., Chan, W., Palomeque, C., Wetmur, J. G., Kabat, G. C., Teitelbaum, S. L., Britton, J. A., Terry, M. B., Neugut, A. I., & Santella, R. M. (2005). One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Research, 65(4), 1606–1614. https://doi.org/10.1158/0008-5472.CAN-04-2630
   PubMed Web of Science ®Google Scholar
• Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., Lee, P. W., & Tang, Y. (2012). admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. Journal of Chemical Information and Modeling, 52(11), 3099–3105. https://doi.org/10.1021/ci300367a
   PubMed Web of Science ®Google Scholar
• Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717. https://doi.org/10.1038/srep42717
   PubMed Web of Science ®Google Scholar
• Dallakyan, S., & Olson, A. J. (2015). Small-molecule library screening by docking with PyRx. Surveys in High Energy Physics, 14(1), 145–173. https://doi.org/10.1080/01422419908228843
   Google Scholar
• Escalante, C. P., & Zalpour, A. (2011). Vascular endothelial growth factor inhibitor-induced hypertension: Basics for primary care providers. Cardiology Research and Practice, 2011, 816897. https://doi.org/10.4061/2011/816897
   PubMedGoogle Scholar
• Froese, D. S., Kopec, J., Rembeza, E., Bezerra, G. A., Oberholzer, A. E., Suormala, T., Lutz, S., Chalk, R., Borkowska, O., Baumgartner, M. R., & Yue, W. W. (2018). Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nature Communications, 9(1), 2261. https://doi.org/10.1038/s41467-018-04735-2
   Web of Science ®Google Scholar
• Goyette, P., Pai, A., Milos, R., Frosst, P., Tran, P., Chen, Z., Chan, M., & Rozen, R. (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mammalian Genome: Official Journal of the International Mammalian Genome Society, 9(8), 652–656. https://doi.org/10.1007/s003359900838
   PubMed Web of Science ®Google Scholar
• Guan, L., Yang, H., Cai, Y., Sun, L., Di, P., Li, W., Liu, G., & Tang, Y. (2019). ADMET-score–A comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm, 10(1), 148–157. https://doi.org/10.1039/C8MD00472B
   PubMed Web of Science ®Google Scholar
• Haiko, P., Makinen, T., Keskitalo, S., Taipale, J., Karkkainen, M. J., Baldwin, M. E., Stacker, S. A., Achen, M. G., & Alitalo, K. (2008). Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Molecular and Cellular Biology, 28(15), 4843–4850. https://doi.org/10.1128/mcb.02214-07
   PubMed Web of Science ®Google Scholar
• Hollingsworth, S. A., & Dror, R. O. (2018). Molecular dynamics simulation for all. Neuron, 99(6), 1129–1143. https://doi.org/10.1016/j.neuron.2018.08.011
   PubMed Web of Science ®Google Scholar
• Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012). Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science (New York, N.Y.), 336(6084), 1040–1044. https://doi.org/10.1126/science.1218595
   PubMed Web of Science ®Google Scholar
• Jarada, T. N., Rokne, J. G., & Alhajj, R. (2020). A review of computational drug repositioning: Strategies, approaches, opportunities, challenges, and directions. Journal of Cheminformatics, 12 (1), 1–23. https://doi.org/10.1186/s13321-020-00450-7
   PubMed Web of Science ®Google Scholar
• Kar, S., & Leszczynski, J. (2020). Open access in silico tools to predict the ADMET profiling of drug candidates. Expert Opinion on Drug Discovery, 15 (12), 1473–1487. https://doi.org/10.1080/17460441.2020.1798926
   PubMed Web of Science ®Google Scholar
• Kaufmann, P., Okubo, K., Bruderer, S., Mant, T., Yamada, T., Dingemanse, J., & Mukai, H. (2015). Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions, 15(3), 195–203. https://doi.org/10.1007/s40256-015-0117-4
   PubMed Web of Science ®Google Scholar
• Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2021). PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Research, 49(D1), D1388–D1395. https://doi.org/10.1093/nar/gkaa971
   PubMed Web of Science ®Google Scholar
• Kim, Y. I. (2009). Role of the MTHFR polymorphisms in cancer risk modification and treatment. Future Oncology (London, England), 5(4), 523–542. https://doi.org/10.2217/fon.09.26
   PubMed Web of Science ®Google Scholar
• Knütter, I., Wollesky, C., Kottra, G., Hahn, M. G., Fischer, W., Zebisch, K., Neubert, R. H. H., Daniel, H., & Brandsch, M. (2008). Transport of angiotensin-converting enzyme inhibitors by H +/peptide transporters revisited. The Journal of Pharmacology and Experimental Therapeutics, 327(2), 432–441. https://doi.org/10.1124/jpet.108.143339
   PubMed Web of Science ®Google Scholar
• Kumar, K. M., Anbarasu, A., & Ramaiah, S. (2014). Molecular docking and molecular dynamics studies on β-lactamases and penicillin binding proteins. Molecular bioSystems, 10(4), 891–900. https://doi.org/10.1039/c3mb70537d
   PubMedGoogle Scholar
• Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993). PROCHECK: a program to check the stereochemical quality of protein structures. Journal of applied crystallography, 26(2), 283–291.
   Google Scholar
• Lazaro, G., Kostaras, E., & Vivanco, I. (2020). Inhibitors in AKTion: ATP-competitive vs allosteric. Biochemical Society Transactions, 48(3), 933–943. https://doi.org/10.1042/BST20190777
   PubMed Web of Science ®Google Scholar
• Lee, T. C., & Threadgill, D. W. (2009). Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis (New York, N.Y. : 2000), 47(2), 85–92. https://doi.org/10.1002/dvg.20464
   PubMed Web of Science ®Google Scholar
• Lindorff-Larsen, K., Piana, S., Palmo, K., Maragakis, P., Klepeis, J. L., Dror, R. O., & Shaw, D. E. (2010). Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins, 78(8), 1950–1958. https://doi.org/10.1002/prot.22711
   PubMed Web of Science ®Google Scholar
• Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development q settings. Advanced Drug Delivery Reviews, 46(1–3), 3–26. www.elsevier.com/locate/drugdeliv https://doi.org/10.1016/S0169-409X(00)00129-0
   PubMed Web of Science ®Google Scholar
• Liu, G. M., Zeng, H. D., Zhang, C. Y., & Xu, J. W. (2019). Identification of a six-gene signature predicting overall survival for hepatocellular carcinoma. Cancer Cell International, 19, 138. https://doi.org/10.1186/s12935-019-0858-2
   Web of Science ®Google Scholar
• Martin, Y. C. (2005). A bioavailability score. Journal of Medicinal Chemistry, 48(9), 3164–3170. https://doi.org/10.1021/jm0492002
   PubMed Web of Science ®Google Scholar
• Masuda, C., Yanagisawa, M., Yorozu, K., Kurasawa, M., Furugaki, K., Ishikura, N., Iwai, T., Sugimoto, M., & Yamamoto, K. (2017). Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model. International Journal of Oncology, 51(2), 425–434. https://doi.org/10.3892/ijo.2017.4036
   PubMed Web of Science ®Google Scholar
• Mattaini, K. R., Sullivan, M. R., & Vander Heiden, M. G. (2016). The importance of serine metabolism in cancer. Journal of Cell Biology, 214 (3), 249–257. https://doi.org/10.1083/jcb.201604085
   PubMed Web of Science ®Google Scholar
• Mazat, J.-P. (2021). One-carbon metabolism in cancer cells: A critical review based on a core model of central metabolism. Biochemical Society Transactions, 49(1), 1–15. https://doi.org/10.1042/BST20190008
   PubMed Web of Science ®Google Scholar
• Miller, B. R. I. I. I., McGee, T. D., Jr., Swails, J. M., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012). MMPBSA.py: An efficient program for end-state free energy calculations. Journal of Chemical Theory and Computation, 8(9), 3314–3321. https://doi.org/10.1021/ct300418h
   PubMed Web of Science ®Google Scholar
• Muegge, I., Heald, S. L., & Brittelli, D. (2001). Simple selection criteria for drug-like chemical matter. Journal of Medicinal Chemistry, 44(12), 1841–1846. https://doi.org/10.1021/jm015507e
   PubMed Web of Science ®Google Scholar
• Naseem, A., Pal, A., Gowan, S., Asad, Y., Donovan, A., Temesszentandrási-Ambrus, C., Kis, E., Gaborik, Z., Bhalay, G., & Raynaud, F. (2022). Intracellular metabolomics identifies efflux transporter inhibitors in a routine Caco-2 cell permeability assay—Biological implications. Cells, 11(20), 3286. https://doi.org/10.3390/cells11203286
   PubMed Web of Science ®Google Scholar
• Newman, A. C., & Maddocks, O. D. K. (2017). One-carbon metabolism in cancer. British Journal of Cancer, 116(12), 1499–1504. https://doi.org/10.1038/bjc.2017.118
   PubMed Web of Science ®Google Scholar
• Nowak-Sliwinska, P., Scapozza, L., & i Altaba, A. R. (2019). Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer. Biochimica et Biophysica Acta - Reviews on Cancer, 1871 (2), 434–454. https://doi.org/10.1016/j.bbcan.2019.04.005
   PubMed Web of Science ®Google Scholar
• Pathania, S., & Singh, P. K. (2021). Analyzing FDA-approved drugs for compliance of pharmacokinetic principles: should there be a critical screening parameter in drug designing protocols?. Expert Opinion on Drug Metabolism and Toxicology, 17 (4), 351–354. https://doi.org/10.1080/17425255.2021.1865309
   PubMed Web of Science ®Google Scholar
• Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera – A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612. https://doi.org/10.1002/jcc.20084
   PubMed Web of Science ®Google Scholar
• Réa, D., & Hughes, T. P. (2022). Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Critical Reviews in Oncology/Hematology, 171, 103580. https://doi.org/10.1016/j.critrevonc.2022.103580
   PubMed Web of Science ®Google Scholar
• Roessler, H. I., Knoers, N. V. A. M., van Haelst, M. M., & van Haaften, G. (2021). Drug repurposing for rare diseases. Trends in Pharmacological Sciences, 42 (4), 255–267. https://doi.org/10.1016/j.tips.2021.01.003
   PubMed Web of Science ®Google Scholar
• Rognan, D. (2017). The impact of in silico screening in the discovery of novel and safer drug candidates. Pharmacology & Therapeutics, 175, 47–66. https://doi.org/10.1016/j.pharmthera.2017.02.034
   PubMed Web of Science ®Google Scholar
• Schein, C. H. (2021). Repurposing approved drugs for cancer therapy. British Medical Bulletin, 137 (1), 13–27. https://doi.org/10.1093/bmb/ldaa045
   PubMed Web of Science ®Google Scholar
• Silva, D., & Vranken, B. F. (2012). ACPYPE-AnteChamber PYthon Parser interfacE. BMC Research Notes, 5(1), 1–8. http://www.biomedcentral.com/1756-0500/5/367
   Google Scholar
• Sneha, P., & Priya Doss, C. G. (2016). Molecular dynamics: New frontier in personalized medicine. Advances in Protein Chemistry and Structural Biology, 102, 181–224. https://doi.org/10.1016/bs.apcsb.2015.09.004
   PubMed Web of Science ®Google Scholar
• Stankova, J., Lawrance, A., & Rozen, R. (2008). Methylenetetrahydrofolate reductase (MTHFR): A novel target for cancer therapy. Current Pharmaceutical Design, 14(11), 1143–1150. https://doi.org/10.2174/138161208784246171
   PubMed Web of Science ®Google Scholar
• Stankova, J., Shang, J., & Rozen, R. (2005). Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 11(5), 2047–2052. https://doi.org/10.1158/1078-0432.CCR-04-2047
   PubMed Web of Science ®Google Scholar
• Sterling, T., & Irwin, J. J. (2015). ZINC 15 – Ligand discovery for everyone. Journal of Chemical Information and Modeling, 55(11), 2324–2337. https://doi.org/10.1021/acs.jcim.5b00559
   PubMed Web of Science ®Google Scholar
• Su, A., Ling, F., Vaganay, C., Sodaro, G., Benaksas, C., Dal Bello, R., Forget, A., Pardieu, B., Lin, K. H., Rutter, J. C., Bassil, C. F., Fortin, G., Pasanisi, J., Antony-Debré, I., Alexe, G., Benoist, J.-F., Pruvost, A., Pikman, Y., Qi, J., … Puissant, A. (2020). The folate cycle enzyme MTHFR is a critical regulator of cell response to MYC-targeting therapies. Cancer Discovery, 10(12), 1894–1911. https://doi.org/10.1158/2159-8290.CD-19-0970
   PubMed Web of Science ®Google Scholar
• Sun, D. F., Weng, Y. R., Chen, Y. X., Lu, R., Wang, X., & Fang, J. Y. (2008). Knock-down of methylenetetrahydrofolate reductase reduces gastric cancer cell survival: An in vitro study. Cell Biology International, 32(8), 879–887. https://doi.org/10.1016/j.cellbi.2008.03.018
   PubMed Web of Science ®Google Scholar
• Tang, Z., Li, C., Kang, B., Gao, G., Li, C., & Zhang, Z. (2017). GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Research, 45(W1), W98–W102. https://doi.org/10.1093/nar/gkx247
   PubMed Web of Science ®Google Scholar
• Tibbetts, A. S., & Appling, D. R. (2010). Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annual Review of Nutrition, 30, 57–81. https://doi.org/10.1146/annurev.nutr.012809.104810
   PubMed Web of Science ®Google Scholar
• Valdés-Tresanco, M. S., Valdés-Tresanco, M. E., Valiente, P. A., & Moreno, E. (2021). gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS. Journal of Chemical Theory and Computation, 17(10), 6281–6291. https://doi.org/10.1021/acs.jctc.1c00645
   PubMed Web of Science ®Google Scholar
• Volkamer, A., Kuhn, D., Rippmann, F., & Rarey, M. (2012). Dogsitescorer: A web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics (Oxford, England), 28(15), 2074–2075. https://doi.org/10.1093/bioinformatics/bts310
   PubMed Web of Science ®Google Scholar
• Vyas, V., Jain, A., Jain, A., & Gupta, A. (2008). Virtual screening: A fast tool for drug design. Scientia Pharmaceutica, 76(3), 333–360. https://doi.org/10.3797/scipharm.0803-03
   Google Scholar
• Wallace, A. C., Laskowski, R. A., & Thornton, J. M. (1995). LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. Protein Engineering, 8 (2), 127–134. http://peds.oxfordjournals.org/
   PubMedGoogle Scholar
• Wang, X., Xu, Z., Ren, X., Chen, X., Yi, Q., Zeng, S., Thakur, A., Gong, Z., & Yan, Y. (2022). MTHFR inhibits TRC8‐mediated HMOX1 ubiquitination and regulates ferroptosis in ovarian cancer. Clinical and Translational Medicine, 12(9), e1013. https://doi.org/10.1002/ctm2.1013
   Web of Science ®Google Scholar
• Wen, Y. C., Chen, W. Y., Tram, V. T. N., Yeh, H. L., Chen, W. H., Jiang, K. C., Abou-Kheir, W., Huang, J., Hsiao, M., & Liu, Y. N. (2022). Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency. Cell Death and Disease, 13(3), 252. https://doi.org/10.1038/s41419-022-04694-z
   Web of Science ®Google Scholar
• Wiederstein, M., & Sippl, M. J. (2007). ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Research, 35(Web Server), W407–W410. https://doi.org/10.1093/nar/gkm290
   PubMed Web of Science ®Google Scholar
• Wu, M. T., Ye, W. T., Wang, Y. C., Chen, P. M., Liu, J. Y., Tai, C. K., Tang, F. Y., Li, J. R., Liu, C. C., & Chiang, E. P. I.. (2021). MTHFR knockdown assists cell defense against folate depletion induced chromosome segregation and uracil misincorporation in DNA. International Journal of Molecular Sciences, 22(17), 9392. https://doi.org/10.3390/ijms22179392
   PubMed Web of Science ®Google Scholar
• Yang, H., Lou, C., Sun, L., L., J., Cai, Y., Wang, Z., Li, W., Liu, G., & Tang, Y. (2017). admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties. Bioinformatics, 33(1), 1–7. https://doi.org/10.1093/bioinformatics/xxxxxx
   PubMedGoogle Scholar
• Yang, L., Wang, X. W., Zhu, L. P., Wang, H. L., Wang, B., Wu, T., Zhao, Q., Jinsihan, D. L. X. T., & Wang, X. Y. (2016). Relationship between genetic polymorphisms of methylenetetrahydrofolate reductase and breast cancer chemotherapy response. Genetics and Molecular Research, 15(3), https://doi.org/10.4238/gmr.15038679
   Google Scholar
• Zhang, Z., Zhou, L., Xie, N., Nice, E. C., Zhang, T., Cui, Y., & Huang, C. (2020). Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy, 5 (1). 1–25. https://doi.org/10.1038/s41392-020-00213-8
   PubMed Web of Science ®Google Scholar
• Zheng, Y., Ramsamooj, S., Li, Q., Johnson, J. L., Yaron, T. M., Sharra, K., & Cantley, L. C. (2019). Regulation of folate and methionine metabolism by multisite phosphorylation of human methylenetetrahydrofolate reductase. Scientific Reports, 9(1), 4190. https://doi.org/10.1038/s41598-019-40950-7
   Google Scholar
• Zhang, L., Zhou, F., Han, W., Shen, B., Luo, J., Shibuya, M., & He, Y. (2010). VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Research, 20(12), 1319–1331. https://doi.org/10.1038/cr.2010.116
   PubMed Web of Science ®Google Scholar
• Zhu, H., Martin, T. M., Ye, L., Sedykh, A., Young, D. M., & Tropsha, A. (2009). Quantitative structure − Activity relationship modeling of rat acute toxicity by oral exposure. Chemical Research in Toxicology, 22(12), 1913–1921. https://doi.org/10.1021/tx900189p
   PubMed Web of Science ®Google Scholar