engleski

In Silico Toxicity Evaluation of Hydroxamic Acid-Based Histone Deacetylase Inhibitors

The aim of this study was to predict the ADMET properties of selected hydroxamic acid-based histone deacetylase inhibitors (HDACIs, n = 31) in order to get more insights in their safety profile. Different physico-chemical and toxicological properties were predicted and analyzed in correlation studies using molecular descriptors (MlogP, TPSA, MW, V and W) and ADMET properties. All parameters were computed by ADMET PredictorTM 8.5 (Simulations Plus, USA). QSAR analyses were performed using OriginPro 8.0 (Origin Laboratories, USA). The majority of investigated HDACIs have been predicted to be both, CYP inhibitors and CYP substrates of CYP 1A2, 2C9, 2D6 and 3A4 ezymes. QSAR studies, using computed molecular descriptors (MDs) and predicted ADMET properties revealed the most significant correlations between Wiener index (W) and ADMET_Risk, Absn_Risk and AP_FWeight (R-squared 0.767 to R = 0.906) and between ADMET_Risk and CYP_Risk, N_CYP Sites, MW, MolVol, as wel as S+LogP (R-squared from 0.728 to 0.820). ADMET_Risks were predicted between 1 and 13 with the following ADMET_Codes: rotatable bonds (RB), size (Sz), overweight (ow), charge (ch), water solubility (Sw), human jejunal permeability (Pf), protein binding (fu), volume distribution (Vd), hepatotoxicity (Hp), mutagenicity (Mu), rat (Xr) and mouse carcinognicity (Xm), excessive clearance by CYP 1A, C9, 3A, and inhibition of testosterone (ti) and midazolam (mi) metabolism by CYP 3A4. Computed CYP_Risks were between 1 and 1.463 (CYP_Codes: 1A, 3A, C9 and D6) and TOX_Risk between 1 and 4.61 (TOX_Codes: mutagenicity (Mu) and hepatotoxicity (Hp), hERG toxicity (hE), rat carcinogenicity (Xr), mouse carcinogenicity (Xm), acute rat toxicity (ra). The results of this study revealed many unfavourable properties of evaluated hydroxamic acid-based HDACIs including hepatotoxicity and mutagenicity as the main characteristic of their toxic profile.

Hydroxamic Acid-based Histone Deacetylase Inhibitors ; HDACI ; Hydroxamic Acid ; ADMET ; Toxicity

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