[Predict of metabolic stability of xenobiotics by the PASS and GUSAR programs].

Metabolic stability refers to the susceptibility of compounds to the biotransformation; it is characterized by such pharmacokinetic parameters as half-life (T1/2) and clearance (CL). Generally, these parameters are estimated by in vitro assays, which are based on cells or subcellular fractions (mainly liver microsomal enzymes) and serve as models of the processes occurring in living organisms. Data obtained from the experiments are used to build QSAR (Quantitative Structure-Activity Relationship) models. More than 8000 compounds with known CL and/or T1/2 values obtained in vitro using human liver microsomes were selected from the freely available ChEMBL v.27 database. GUSAR (General Unrestricted Structure-Activity Relationships) and PASS (Prediction of Activity Spectra for Substances) softwares were used to make quantitative and classification models. The quality of the models was evaluated using 5-fold cross-validation. Compounds were subdivided into "stable" and "unstable" by means of the following threshold parameters: T1/2 = 30 minutes, CL = 20 ml/min/kg. The accuracy of the models ranged from 0.5 (calculated in 5-fold CV on the test set for the half-life prediction quantitative model) to 0.96 (calculated in 5-fold CV on the test set for the clearance prediction classification model). Metabolicheskaia stabil'nost' opredeliaet stepen' ustoĭchivosti lekarstvenno-podobnykh soedineniĭ k biotransformatsii v organizme cheloveka i kharakterizuetsia takimi farmakokineticheskimi parametrami kak period poluvyvedeniia (T1/2) i klirens (CL). Kak pravilo, dlia ikh otsenki ispol'zuiutsia in vitro sistemy na osnove kletok ili subkletochnykh fraktsiĭ (v osnovnom mikrosomal'nye fermenty pecheni), kotorye sluzhat modeliami protsessov, protekaiushchikh v zhivom organizme. Poluchennye v rezul'tate éksperimentov dannye ispol'zuiutsia dlia postroeniia QSAR (Quantitative Structure-Activity Relationship) modeleĭ. Na osnove svobodno dostupnoĭ bazy dannykh ChEMBL v.27 bylo otobrano bolee 8000 zapiseĭ, soderzhashchikh struktury soedineniĭ i znacheniia ikh klirensa i/ili perioda poluvyvedeniia, poluchennye in vitro na mikrosomakh pecheni cheloveka. Dlia polucheniia kolichestvennykh i klassifikatsionnykh modeleĭ bylo ispol'zovano programmnoe obespechenie GUSAR (General Unrestricted Structure-Activity Relationships) i PASS (Prediction of Activity Spectra for Substances). Dlia otsenki kachestva modeleĭ ispol'zovalas' 5-kratnaia perekrestnaia proverka. Dlia razdeleniia soedineniĭ na stabil'nye i ne stabil'nye byli vybrany porogi T1/2=30 min, CL=20 ml/min/kg. Tochnost' modeleĭ var'iruetsia ot 0,5 (poschitano na testovoĭ vyborke dlia kolichestvennoĭ modeli prognoza vremeni poluvyvedeniia pri 5-kratnoĭ perekrestnoĭ proverke) do 0,96 (poschitano na testovoĭ vyborke dlia klassifikatsionnoĭ modeli prognoza klirensa pri 5-kratnoĭ perekrestnoĭ proverke).