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Retinoic Acid Activity on Mamalian Embryo in Organ Culture and Evaluation of Hazard and Risk in Correlation Studies between Molecular Descriptors and ADMET Parameters in a Series od X-Category Drugs

The results of our previous work on mammalian embryo-derived teratomas in organ culture treated with either retinoic acid (RA, c = 10-5 mol/L) or neural growth factor (NGF, 100 ng/mL) showed no influence on neural tissue differentiation. On the contrary the combination of RA and NGF influenced neural tissue differentiation (100%) and inhibition of other tissues (epidermis, gland epithelium, cartilage). The influence of RA, either alone or in presence of NGF on potential teratogenicity has been revealed in this model. In continuation of this work we have explored the molecular features of retinoids in a series of selected X-category drugs in correlation studies between computed molecular descriptors (MDs) and ADMET parameters. Computed MDs and ADMET parameters of 37 drug molecules were predicted by MedChem ADMET Predictor Module (Simulations Plus. Inc. USA). All correlation analyses were performed using OriginPro 8.0 software (Origin Laboratories, USA). Most investigated molecules were amides or lactams with the possibility of biotransformation to corresponding acids. Interesting relationships were obtained in correlations of computed lipophilicity (MLog P) and total polar surface area (TPSA) with hERG toxicity (TOX hERG), i.e. MLogP v.s TOX hERG (y = 0.619x + 3.918, r = 0.977), and TPSA v.s. hERG (y =-0.016x + 7.024, r = 0.912). In both correlations, a two sets of molecules were observed, one with high collinear relationship between TOX hERG with either MLogP or TPSA, while the other set was a cluster of diverse X-category drugs. For all retinoids included in this study, the ADMET Risk of 4, TOX Risk of 2, while TOX MUT Risk of 1 for retinol and etretinate, were predicted.

Embryo-derived teratomas; Retinoic acid; Retinouds; X-Category drugs; ADMET; Molecular descriptors; Drug-likeness; Toxicity; QSAR

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