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The study of ADMET properties of drug candidates has become essential in the drug development process since almost half of drug candidates fail during the development process due to an inappropriate pharmacokinetic profile (1). Metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug consequently have important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage due to metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism (2, 3). The aim of this in silico study was to predict the cytochrome P450 (CYP) metabolism of substituted 2-oxindole derivatives that were previously synthesized and tested on tyrosine kinase activity (4-6). For that purpose the ADMET PredictorTM, SimulationsPlus Inc., USA was used with its Metabolism module, i.e., CYP substrate/non substrate classification models for CYP isoforms 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4, their corresponding site of metabolism models (SOM) as well as kinetic parameter models (Km, Vmax and Clint) and CYP inhibition models for 1A2, 2C9, 2C19, 2D6, and 3A4. Metabolites were generated using SMIRKS strings (a reaction transform language) to specify the transformations predicted by the SOM models. The CYP kinetic parameters were predicted from ANNE regression models. The results of this study revealed an extensive CYP metabolism of 2-oxindole derivatives mediated mainly by three CYP isoforms (2C9, 2D6 and 3A4) with percentage of metabolized molecules as it follows: CYP3A4_Substr> CYP2C9_Substr> CYP2D6_Substr (81.8% > 31.8% > 27.3%, respectively) and CYP2C9_Inh > CYP3A4_Inh > (86.6% > 29.5% > 4.5%, respectively). The inhibition of testosterone metabolism by CYP3A4 was predicted for 32 of 44 molecules (CYP3A4_Inh 72.7%) which could have an implication of potential drug—drug interactions of these compounds. The most represented metabolic reactions mediated by CYPs were: aromatic hydroxylation, oxidative N-dealkylation of di-substituted urea- and thiourea-2-oxindoles to their corresponding mono-substituted metabolites. For all thiourea derivatives the reaction of desulphuration was also predicted by which -NH-C(=S)-NH- moiety was converted into urea moiety what implies a potential pro-drug use of thiourea-2-oxindoles. However, for all thiourea-2-oxindoles the highest CYP_Risk scores and TOX_Risks, including mutagenicity and/or carcinogenicity were also predicted. References: 1. Jones BC, Middleton DS, Youdim K. Prog Med Chem 2009 ; 47:239–263. 2. Andrade HC, Silva CD, Braga CR. Curr Drug Metab 2014 ; 15:514-525. 3. Kirchmair J, Göller AH, Lang D, Kunze J, Testa B, Wilson ID, Glen RC, Schneider G. Nat Rev Drug Discov 2015 ; 14:387-404 4. Kilic-Kurt Z, Bakar F, Olgen S. Arch Pharm Chem Life Sci 2015 ; 348:1–15 ; 5. Kilic-Kurt Z, Onay-Besikci A, Olgen S. LDDD 2013 ; 10:713-718 ; 6. Kılıc Z, Isgor YG, Olgen S. Arch Pharm 2009 ; 342:333-343. |
