Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Click here for more information

Sign In to gain access to subscriptions and/or personal tools.
Journal of Biomolecular Screening
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
1087057109336751v1
14/8/913    most recent
Right arrow References
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Krippendorff, B.-F.
Right arrow Articles by Huisinga, W.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krippendorff, B.-F.
Right arrow Articles by Huisinga, W.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

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

Ben-Fillippo Krippendorff

Hamilton Institute, National University of Ireland Maynooth, Ireland, and International Max-Planck Research School for Computational Biology and Scientific Computing, Berlin, Germany

Roland Neuhaus

Bayer Schering Pharma AG, Department of Research Pharmacokinetics, Berlin, Germany

Philip Lienau

Bayer Schering Pharma AG, Department of Research Pharmacokinetics, Berlin, Germany

Andreas Reichel

Bayer Schering Pharma AG, Department of Research Pharmacokinetics, Berlin, Germany

Wilhelm Huisinga

Hamilton Institute, National University of Ireland Maynooth, Ireland, and International Max-Planck Research School for Computational Biology and Scientific Computing, Berlin, Germany, wilhelm.huisinga{at}nuim.ie

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)

Key Words: irreversible inhibition • time-dependent IC50 values • Cheng-Prusoff relation

This version was published on September 1, 2009

Journal of Biomolecular Screening, Vol. 14, No. 8, 913-923 (2009)
DOI: 10.1177/1087057109336751
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?