P450-mediated metabolism of drugs is a major process controlling their clearance as well as toxicity. Medium to high-thoughput predictive methods are highly desirable for efficient drug design. We will present our efforts leading to Impacts (In-silico Metabolism Prediction by Activated Cytochromes and Transition States), a computational tool combining docking to metabolic enzymes, transition state modeling and rule-based substrate reactivity prediction. Its development will first be described followed by its validation on carefully developed sets of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Further studies assessing it assignificance will also be described. More specifically, we investigated whether our method rivals biotransformation experts'.

Computational method for the prediction of P450-mediated metabolism: Development, validation, and significance

244th National Meeting (2012)

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