| Thiazole ring is an important active molecular skeleton in drugs.Thiazole is generally harmless in natural products and medicines.However,hepatotoxicity may occur if thiazole produces active metabolite thioamide during the biological activation process.A typical example is hepatotoxic sudoxicam and safety meloxicam.The only structural difference between them is a methyl group on C5 position of thiazole in meloxicam.The reason for the difference in the safety of the two drug molecules caused by the methyl group is not clear,and the biological activation mechanism of the thiazole ring is also unclear.Therefore,we explored the activation mechanism of the thiazole ring when Cyptochrome P450 Compound I(Cpd I)attacked different sites through quantum chemical calculations,and studied the influence of substituents on the activation pathway of the thiazole ring.When Cpd I attacks C5,the activation process of thiazole is closely related to the type of substituents and the spin state of Cpd I.When Cpd I is in the doublet state,the thiazole and substituted thiazoles are catalyzed to directly open the ring.When Cpd I is in the quartet state,they can be catalyzed to open the ring directly or through the Fe-O-C5 intermediate.The specific ring-opening process is related to the nature of the substituents,that is,thiazoles modified with electron-donating substituents mainly undergo direct ring opening,and thiazoles modified with electron-withdrawing groups or weak electron-donating groups mainly undergo ring opening process through intermediate.When Cpd I attacks C4,the activation process of thiazole is only related to the spin state of Cpd I and not to the type of substituents.When the doublet state Cpd I catalyzes thiazole,the Fe-O-C4 intermediate is formed first and then the ring is opened.When the quartet state Cpd I catalyzes the thiazole,it does not undergo the intermediate but a one-step epoxidation.The energy barriers of Cpd I attacking C5 in both spin state are lower than those of C4,so the reaction path through the C5 site is more advantageous.In general,the Gibbs free energy barriers of each step in the metabolism of meloxicam and sudoxicam to the active substance thioamide are relatively close,so the hydroxylation of the C5 methyl group on the meloxicon thiazole ring is the main reason for the difference in the nature of the two.The above research based on quantum chemistry has laid a foundation for the drug metabolism and drug design,and also laid a theoretical foundation for the study of reducing the toxicity of thiazole ring drugs.Dug-induced liver injury(DILI)is a key issue in the development of drug,because DILI is harmful to human and can cause clinical trials to fail.A large number of calculations have shown that in silicon models have good utility in evaluating the toxicity of drug candidates.These methods predict toxicity by evaluating various characteristics of drugs.We screened out 663 compounds related to liver toxicity and randomly divided them into training set and test set according to the ratio of 9:1,and calculated MACCS fingerprints,CDK fingerprints,CDK extended fingerprints,Estate fingerprints,Pubchem fingerprints,Substructure fingerprints and molecular descriptor.The prediction models were built with machine learning methods such as random forests(RF),support vector machine(SVM),naive bayes(NB),K-Nearest Neighbor(k NN),artificial neural network(ANN).The results show that Pubchem fingerprint combined with artificial neural network(ANN)and molecular descriptor combined with random forest(RF)have good prediction results.Their(Area Under the receiver operating characteristic Curve)AUC values are 0.888 and 0.831,and the accuracy(CA)values are 0.844 and 0.766,respectively.The structural alerts in toxic drugs were build by fragment-based method,such as thiazole ring,furan ring,aniline,etc.,which provides a basis for drug design and drug metabolism research. |
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