Sukhachev V. S. , Ivanov S. M. , Filimonov D. A. , Poroikov V. V. Alternative Methods of Studies. Computer-Aided Estimation of Rodents Acute Toxicity. Laboratory Animals for Science. 2019; 4. https://doi.org/10.29296/2618723X-2019-04-04
The determination of LD50 values in rodents is the mandatory stage of experimental preclinical studies of pharmacological substances. We implemented in silico estimation of the LD50 value for substance with four routes of administration (intraperitoneal, intravenous, oral, subcutaneous) using GUSAR (General Unrestricted Structure-Activity Relationships) computer program. Both the stand-alone version (for rats and mice) and a web service freely available through the Internet (for rats) are developed. During the prediction of the LD50 value for the analyzed compound, its belonging to the applicability domain of the used QSAR model is estimated. The corresponding information is provided to the investigator. Using the prediction of the LD50 value for the local anesthetic Procaine (Novocaine), the possibilities and limitations of computer estimation of acute toxicity are demonstrated. In the absence of experimental LD50 values, it is possible to use the calculated values obtained with the built QSAR models, since by comparison of known experimental and calculated values in most cases we found that classification of hazard is the same in both cases. An analysis of the availability of experimental data on the acute toxicity of several local anesthetics (Benzocaine, Butamben, Chloroprocaine hydrochloride) for mice and rats in the ChemIDplus information system showed that these data are presented only for some routes of drug administration. We supplemented the corresponding “gaps” in the data with the estimated values obtained based on the GUSAR models. Also, we developed the method of generating a xenobiotic metabolism network in the human body, for fifteen types of biotransformation reactions carried out by the eight major cytochrome P450 isoforms and various transferases, hydrolases, and esterases involved in the xenobiotic metabolism. Combining this method and the developed QSAR models, we created a public web resource MetaTox (http://www.way2drug.com/mg), which provides an integrated assessment of xenobiotics toxicity based on the structures of the parent compound and its metabolites. Using computer prediction, the safer compounds may be selected for experimental testing of acute toxicity among various substances with the required pharmacological effect, which reduces the number of experiments in laboratory animals.
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