The investigation of drug repurposing for HDAC1 inhibitory effects by in silico and in vitro methods

Yıl 2023, Cilt: 53 Sayı: 3, 287 - 293, 28.12.2023

Hüseyin İstanbullu , Ezgi Turunç , Sami Hamdoun , Merve Saylam , Halil Koyu , Tijen Kaya-temiz

https://doi.org/10.26650/IstanbulJPharm.2023.1269175

Öz

Background and Aims:Histone deacetylases (HDACs) modulate chromatin structure and regulate gene expression. The imbalance in chromatin acetylation and dysregulation of histone deacetylases are challenging in many pathologies, ranging from cancer to neurodegeneration. Computer-based in silico methods are becoming increasingly important in the determination of therapeutic targets and the development of personalized treatment approaches. This study aimed to investigate the HDAC1 inhibitory effects of chronic prescription drugs using in silico and in vitro methods.

Methods:Five chronically used prescription drugs were chosen: ipratropium bromide, metoprolol, leflunomide, nateglinide, and levothyroxine. Molecular docking was performed for each of the chosen drugs as well as the known inhibitor Trichostatin A on HDAC1. The binding pose with the best scores was saved for each compound and analyzed for its interaction with the protein. An HDAC1 inhibitor screening assay kit was used to determine the IC50 value for each drug.

Results:The IC50 values for HDAC1 inhibition by ipratropium bromide, metoprolol, leflunomide, nateglinide, and levothyroxine were found to be 352.10 μM, 255.70 μM, 219.80 μM, 289.50 μM, and 132.70 μM, respectively, whereas the value for the positive control Trichostatin A was 36.13 nM. GraphPad Prism 5 was used to conduct statistical analyses.

Conclusion:In this study, the in vitro HDAC1 inhibitory effect of ipratropium bromide, metoprolol, leflunomide, nateglinide, and levothyroxine is shown for the first time. In silico and in vitro methodologies used to show HDAC1 inhibitory activity in marketed drugs can provide insight into new drug discovery studies against cancer or neurodegenerative diseases.

Anahtar Kelimeler

Docking, drug repurposing, HDAC1, in silico, molecular modeling

Destekleyen Kurum

Izmir Katip Celebi University Scientific Research Coordinatorship

Proje Numarası

2018-ONAP-TIPF-0008

Teşekkür

The authors thank all study participants for their cooperation and the institutions for their support. The authors extend their appreciation to the Izmir Katip Celebi University Scientific Research Coordinatorship.

Kaynakça

• Bahari-Javan, S., Varbanov, H., Halder, R., Benito, E., Kaurani, L., Burkhardt, S.... Fischer, A. (2017). HDAC1 links early life google scholar
• stress to schizophrenia-like phenotypes. Proceedings of the Na-tional Academy of Sciences of the USA, 6;114(23):E4686-E4694. https://doi.org/10.1073/pnas.1613842114 google scholar
• Boyd, A. S. (2012). Leflunomide in dermatology. Journal of the American Academy of Dermatology, 66(4):673-679. https://doi.org/10.1016/j.jaad.2011.08.025 google scholar
• Cacabelos, R., Torrellas, C. (2014). Epigenetic drug discovery for Alzheimer’s disease. Expert Opinion Drug Discovery, 9(9):1059-1086. https://doi.org/10.1517/17460441.2014.930124 google scholar
• Cordeiro, A., de Souza, L. L., Oliveira, L. S., Faustino, L. C., Santiago, L. A., Bloise, F. F.... Pazos-Moura, C. C. (2013). Thyroid google scholar
• hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice. Journal of Endocrinology, 216(2):181-193. https://doi.org/10.1530/JOE-12-0420 google scholar
• Dovey, O. M., Foster, C. T., Cowley, S. M. (2010). His-tone deacetylase 1 (HDAC1), but not HDAC2, controls em-bryonic stem cell differentiation. Proceedings of the Na-tional Academy of Sciences of the USA, 107(18):8242-8247. https://doi.org/10.1073/pnas.100047810 google scholar
• Ganai, S. A., Abdullah, E., Rashid, R., Altaf, M. (2017). Com-binatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurolog-ical Disorders. Frontiers in Molecular Neurosciences, 10:357. https://doi.org/10.3389/fnmol.2017.00357 google scholar
• Gao, Q., Yao, P., Wang, Y., Yao, Q., Zhang, J. (2022). Discovery of potent HDAC2 inhibitors based on virtual screening in combi-nation with drug repurposing. Journal of Molecular Structure, 1247(5):131399. https://doi.org/10.1016/j.molstruc.2021.131399 google scholar
• Grassi, G. (2018). Metoprolol in the treatment of car-diovascular disease: a critical reappraisal. Current Medical Research and Opinion, 34(9):1635-1643. https://doi.org/10.1080/03007995.2018.1479245 google scholar
• Guan, M., Fousek, K., Chow, W.A. (2012). Nelfinavir inhibits regu-lated intramembrane proteolysis of sterol regulatory element bind-ing protein-1 and activating transcription factor 6 in castration-resistant prostate cancer. The FEBS Journal, 279(13):2399-2411. https://doi.org/10.1111/j.1742-4658.2012.08619.x google scholar
• Halas, C. J. (2001). Nateglinide. American Jour-nal of Health System Pharmacy, 58(13):1200-1205 https://doi.org/10.1093/ajhp/58.13.1200 google scholar
• Hirata, Y., Sasaki, T., Kanki, H., Choong, C. J., Nishiyama, K., Kubo, G.... Uesato S. (2018). New 5-Aryl-Substituted 2- google scholar
• Aminobenzamide-Type HDAC Inhibitors with a Diketopiper-azine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death. Scientific Reports, 8(1):1400. https://doi.org/10.1038/s41598-018-19664-9 google scholar
• laniro, G., Mangiola, F., Di Rienzo, T.A., Bibbo, S., Franceschi, F., Greco, A.V., Gasbarrini, A. (2014). Levothyroxine absorption in health and disease, and new therapeutic perspectives. European Review for Medical and Pharmacological Sciences, 18(4):451-456. google scholar
• Johnstone, R.W. (2002). Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Reviews Drug Discovery, 1(4):287-299. https://doi.org/10.1038/nrd772 google scholar
• Kazi, A. A., Reddy, B. V. S., Singh, L. R. (2021). Synthetic ap-proaches to FDA approved drugs for asthma and COPD from 1969 to 2020. Bioorganic & Medicinal Chemistry 41:116212. https://doi.org/10.1016/j.bmc.2021.116212 google scholar
• Kitchen, D.B., Decornez, H., Furr, J. R., Bajorath, J. (2004). Dock-ing and scoring in virtual screening for drug discovery: methods and applications. Nature Reviews Drug Discovery, 3(11):935-949. https://doi.org/10.1038/nrd1549 google scholar
• Lardenoije, R., latrou, A., Kenis, G., Kompotis, K., Steinbusch, H. W. M., Mastroeni, D.... Rutten, B. P. F. (2015). The epigenetics of aging and neurodegeneration. Progress in Neurobiology, 131:21-64. https://doi.org/10.1016/j.pneurobio.2015.05.002 google scholar
• Li, Q., Huang, K., Ma, T., Lu, S., Tang, S., Wu, M., Yang, H., Zhong, J. (2022). Metoprolol Protects Against Arginine Vasopressin-Induced Cellular Senescence in H9C2 Cardiomyocytes by Reg-ulating the Sirt1/p53/p21 Axis. Cardiovascular Toxicology, 22(2):99-107. https://doi.org/10.1007/s12012-021-09704-8 google scholar
• Li, Y.Y., Jones, S. J. (2012). Drug repositioning for personalized medicine. Genome Medicine, 4(3):27. https://doi.org/10.1186/gm326 google scholar
• Lindemann, R. K., Gabrielli, B., Johnstone, R.W. (2004). Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle, 3(6):777-786. https://doi.org/10.4161/cc.3.6.927 google scholar
• Lindemann, R. K., Gabrielli, B., Johnstone, R.W. (2004). Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle, 3(6):777-786. https://doi.org/10.4161/cc.3.6.927 google scholar
• Müller, B. M., Jana, L., Kasajima, A., Lehmann, A., Prinzler, J., Budczies, J.... Denkert, C. (2013). Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer-overexpression of HDAC2 and HDAC3 is associated with clin-icopathological indicators of disease progression. BMC Cancer, 13:215. https://doi.org/10.1186/1471-2407-13-215 google scholar
• Park, H., Kim, S., Kim, Y.E., Lim, S.J. (2010). A structure-based virtual screening approach toward the discovery of histone deacetylase inhibitors: identification of promis-ing zinc-chelating groups. ChemMedChem., 5(4):591-597. https://doi.org/10.1002/cmdc.200900500 google scholar
• Park, S. Y., Kim, J. S. (2020). A short guide to his-tone deacetylases including recent progress on class II en-zymes. Experimental & Molecular Medicine, 52(2):204-212. https://doi.org/10.1038/s12276-020-0382-4 google scholar
• Pushpakom, S., Iorio, F., Eyers, P.A., Escott, K.J., Hopper, S., Wells, A.... Pirmohamed, M. (2019). Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1):41-58. https://doi.org/10.1038/nrd.2018.168 google scholar
• Serebryannyy, L.A., Cruz, C.M., de Lanerolle, P. (2016). A Role for Nuclear Actin in HDAC 1 and 2 Regulation. Scientific Reports, 6:28460. https://doi.org/10.1038/srep28460 google scholar
• Spiegel, S., Milstien, S., Grant, S. (2012). Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene. 31(5):537-551. https://doi.org/10.1038/onc.2011.267 google scholar
• Taunton, J., Hassig, C.A., Schreiber, S. L. (1996). A mam-malian histone deacetylase related to the yeast tran-scriptional regulator Rpd3p. Science. 272(5260):408-411. https://doi.org/10.1126/science.272.5260.408 google scholar
• Vishwakarma, S., Iyer, L.R., Muley, M., Singh, P.K., Shastry, A., Saxena, A., Narayanan, S. (2013). Tubastatin, a selective his-tone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. International Immunopharmacology, 16(1):72-78. https://doi.org/10.1016/j.intimp.2013.03.016 google scholar
• Wang, J., Yu, J.T., Tan, M.S., Jiang, T., Tan, L. (2013). Epigenetic mechanisms in Alzheimer’s disease: implications for pathogen-esis and therapy. Ageing Research Reviews, 12(4):1024-1041. https://doi.org/10.1016/j.arr.2013.05.003 google scholar