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Mechanism-Based Inhibition: Deriving KI and kinact Directly from Time-Dependent IC50 Values

The potential of enzyme inhibition of a drug is frequently quantified in terms of IC50 values. Although this is a suitable quantity for reversible inhibitors, concerns arise when dealing with irreversible or mechanism-based inhibitors (MBIs). IC50 values of MBIs are time dependent, causing serious problems when aiming at ranking different compounds with respect to their inhibitory potential. As a consequence, most studies and ranking schemes related to MBIs rely on the inhibition constant (KI) and the rate of enzyme inactivation (kinact) rather than on IC50 values. In this article, the authors derive a novel relation between potentially time-dependent IC 50 values and KI, kinact parameters for different types of inhibition. This allows for direct estimation of KI and kinact values from time-dependent IC50 values, even without the need of additional preincubation experiments. The application of this approach is illustrated using a fluorimetric assay to access the drug-drug interaction potential associated with new chemical entities. The approach can easily be implemented using standard software tools (e.g., XLfit) and may also be suitable for applications where mechanism-based inhibition is a desired mode of action (e.g., at particular pharmacological drug targets). (Journal of Biomolecular Screening 2009:913-923)