Nalazite se na CroRIS probnoj okolini. Ovdje evidentirani podaci neće biti pohranjeni u Informacijskom sustavu znanosti RH. Ako je ovo greška, CroRIS produkcijskoj okolini moguće je pristupi putem poveznice www.croris.hr
izvor podataka: crosbi !

In silico toxicity study of hydroxamic acid-based histone deacetylase inhibitors (CROSBI ID 680544)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | domaća recenzija

Jadrijević-Mladar Takač, Milena ; Morić, Sandra ; Takač, Tin In silico toxicity study of hydroxamic acid-based histone deacetylase inhibitors // Knjiga sažetaka - 8. Simpozij studenata farmacije i medicinske biokemije (FARMEBS 2019) / Bojić, Mirza ; Samoborac Bačura, Anita (ur.). Zagreb: Farmaceutsko-biokemijski fakultet Sveučilišta u Zagrebu, 2019. str. 40-40

Podaci o odgovornosti

Jadrijević-Mladar Takač, Milena ; Morić, Sandra ; Takač, Tin

engleski

In silico toxicity study of hydroxamic acid-based histone deacetylase inhibitors

Hydroxamic acids are the most widely explored class of histone deacetylases inhibitors (HDACIs) as anticancer drugs. Vorinostat was the first HDACI approved by the FDA for treating cutaneous T-cell lymphoma, and recently, numerous HDACIs have been synthesized and several novel compounds are in clinical trials. However, there is only limited clinical experience with toxicities of HDACIs [1, 2, 3]. The aim of this study was to predict the ADMET properties of selected HDACIs (n = 31) in order to get more insights in their safety profile. Different molecular descriptors (MDs) and ADMET properties were computed and analyzed in correlation studies. All parameters were computed and QSAR analysis was performed by ADMET PredictorTM (Simulations Plus, USA). The majority of investigated HDACIs have been predicted to be both, CYP inhibitors and CYP substrates of CYP 1A2, 2C9, 2D6 and 3A4 enzymes. QSAR studies, using computed MDs and ADMET properties, revealed the most significant linear correlations between Wiener index (W) vs. ADMET_Risk (y = 0.001x – 0.114, R = 0.876, p < 0.05, R2 = 0.767, RMSE = 1.495, MAE = 1.170), and vs. Absn_Risk (y = 0.001x – 0.596, R = 0.9476, p < 0.05, R2 = 0.8980, RMSE = 0.450, MAE = 0.341). Significant linear correlations were also revealed between ADMET_Risk vs. Absn_Risk (y = 1.996x + 1.133, R = 0.907, p < 0.05, R2 = 0.822, RMSE = 1.308, MAE = 1.122), vs. CYP_Risk (y = 2.728x + 0.5570, R = 0.900, p < 0.05, R2 = 0.810, RMSE = 1.350, MAE = 1.090), vs. MWt (y = 0.029x - 7.785, R = 0.885, p < 0.05, R2 = 0.784, RMSE = 1.439, MAE = 1.142) and vs. lipophilicity, S+LogP (y = 2.480x - 3.250, R = 0.8402, p < 0.05 ; R2 = 0.706, RMSE = 1.682, MAE = 1.3052). ADMET_Risks were computed between 1 and 13, CYP_Risks between 1 and 1.463 while TOX_Risks between 1 and 4.61. Among many risk codes, the hepatotoxicity (Hp), mutagenicity (Mu), rat (Xr) and mouse carcinognicity (Xm), hERG toxicity, as well as inhibition of testosterone (ti) and midazolam (mi) metabolism by CYP 3A4, were also predicted. The results of this study revealed many unfavorable properties of evaluated hydroxamic acid-based HDACIs including Hp and Mu, the main characteristic of their toxic profile. J. Park, M. Terranova-Barberio, A. Y. Zhong, S. Thomas, P. N. Munster. Clinical Applications of Histone Deacetylase Inhibitors. In Handbook of Epigenetic, The New Molecular Medical Genetics, 2nd Ed., Trygve O. Tollesbol (ed.), Academic Press, Elsevier, 2017, 605–621. P. Bose, Y. Dai, S. Grant. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol Ther 143 (2014) 323–336. S. Subramanian, S.E. Bates, J. J. Wright, I. Espinoza-Delgado, R. L. Piekarz, Clinical Toxicities of Histone Deacetylase Inhibitors. Pharmaceuticals 3 (2010) 2751-2767.

hystone deacetylase inhibitors, anticancer drugs, HDACI, ADMET, toxicity

Rad je priređen s diplomandicom studija Farmacije na Farmaceutsko-biokemijskom fakultetu i studentom studija Kemija i inženjerstvo materijala, Fakultet kemijskog inženjerstva i tehnologije Sveučilišta u Zagrebu

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

Podaci o prilogu

40-40.

2019.

nije evidentirano

objavljeno

978-953-8273-01-8

Podaci o matičnoj publikaciji

Knjiga sažetaka - 8. Simpozij studenata farmacije i medicinske biokemije (FARMEBS 2019)

Bojić, Mirza ; Samoborac Bačura, Anita

Zagreb: Farmaceutsko-biokemijski fakultet Sveučilišta u Zagrebu

Podaci o skupu

8. simpozij studenata farmacije i medicinske biokemije (FARMEBS 2019)

poster

01.06.2019-01.06.2019

Zagreb, Hrvatska

Povezanost rada

Farmacija, Kemija