, Volume 18, Issue 5, pp 2065-2078

Combination of docking, molecular dynamics and quantum mechanical calculations for metabolism prediction of 3,4-methylenedioxybenzoyl-2-thienylhydrazone

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In modern drug discovery process, ADME/Tox properties should be determined as early as possible in the test cascade to allow a timely assessment of their property profiles. To help medicinal chemists in designing new compounds with improved pharmacokinetics, the knowledge of the soft spot position or the site of metabolism (SOM) is needed. In silico methods based on docking, molecular dynamics and quantum chemical calculations can bring us closer to understand drug metabolism and predict drug–drug interactions. We report herein on a combined methodology to explore the site of metabolism prediction of a new cardioactive drug prototype, LASSBio-294 (1), using MetaPrint2D to predict the most likely metabolites, combined with structure-based tools using docking, molecular dynamics and quantum mechanical calculations to predict the binding of the substrate to CYP2C9 enzyme, to estimate the binding free energy and to study the energy profiles for the oxidation of (1). Additionally, the computational study was correlated with a metabolic fingerprint profiling using LC-MS analysis. The results obtained using the computational methods gave valuable information about the probable metabolites of (1) (qualitatively) and also about the important interactions of this lead compound with the amino acid residues of the active site of CYP2C9. Moreover, using a combination of different levels of theory sheds light on the understanding of (1) metabolism by CYP2C9 and its mechanisms. The metabolic fingerprint profiling of (1) has shown that the metabolites founded in highest concentration in different species were metabolites M1, M2 and M3, whereas M8 was found to be a minor metabolite. Therefore, our computational study allowed a qualitative prediction for the metabolism of (1). The approach presented here has afforded new opportunities to improve metabolite identification strategies, mediated by not only CYP2C9 but also other CYP450 family enzymes.


Workflow for metabolic investigation proposed in our work. (a) Proposed computational methods to improve drug metabolism studies using different levels of theory, showing the energy changes from substrate binding to product formation in CYP450-catalyzed drug metabolism. (b) Metabolic fingerprint workflow for complex matrix analysis from different species. Stage I: the preparation of the samples to be analyzed by LC-MS; Stage II: analyze the samples into LC-MS and treat the data; and Stage III: identify and quantify all detectable metabolites produced in vitro by filamentous fungi and discover the similarity across the species using PCA analysis