The results are posted on http://www.virtualtoxlab.org. Fig. 14 shows four selected examples. According Buparlisib in vivo to our calculations, E121 (citrus red 2; a food dye, classified as class 2B carcinogen) displays an affinity of 420 nM towards the AhR, a protein known to trigger chloracne
and related diseases (see, for example, Okey et al., 1994). The overall toxic potential is estimated at 0.471, indicating a moderate risk at exposure or intoxication (orange skins). Dehydrochloromethyltestosterone (DHCMT) has been systematically applied to athletes in the former German Democratic Republic with tragic consequences for some. The VirtualToxLab calculates the binding affinity of DHCMT toward the AR to 11 nM and estimates the toxic potential to 0.545. In the past, drospirenone, an oral contraceptive has frequently been in the news. According to our simulations, it not only binds to the progesterone receptor (36 nM) and the estrogen receptor β (310 nM) but also to the GR (43 nM). The overall toxic potential is estimated at 0.640, which should be definitely interpreted as a toxic alert. Bisphenol A, a known endocrine disrupter would mainly seem to bind to the estrogen receptor β (54 nM; exp. = 93 nM); substantial affinities are also computed toward the GR (1.3 μM) and the estrogen receptor α (8.0 μM). The find more overall toxic potential is estimated to 0.484, suggesting a moderate
risk, particularly at prolonged exposure Table 2. The VirtualToxLab—an in silico technology developed at the Biographics Laboratory 3R, Basel—allows predicting the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. It is based on an automated protocol that simulates and quantifies the binding of any small molecule towards a series of 16 proteins known or suspected to trigger adverse effects: the androgen, aryl hydrocarbon, estrogen α, estrogen β, glucocorticoid, hERG, liver X, mineralocorticoid, progesterone, thyroid α,
thyroid β and PAK5 the peroxisome proliferator-activated receptor γ as well as the enzymes cytochrome P450 1A2, 2C9, 2D6 and 3A4. The toxic potential is derived from the binding affinities to these 16 target proteins, ranges from 0.0 (none) to 1.0 (extreme) and may be interpreted as a toxic alert. The three-dimensional structure of compounds to be tested can generated using the embedded model builder or imported from external sources. The results can be inspected in real-time 3D or downloaded (coordinates of the protein–ligand complexes in PDB format) and analyzed by third-party software. The graphical user interface supports all major operating systems (Mac OS X, Linux, Windows). The calculation of the toxic potential of a compound depends on its size and conformational flexibility.