Journal
ANALYTICAL BIOCHEMISTRY
Volume 409, Issue 2, Pages 163-175Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ab.2010.10.028
Keywords
Biosensor; Surface plasmon resonance (SPR); Human serum albumin (HSA); alpha(1)-Acid glycoprotein (AGP); Serum protein; Binding efficiency
Funding
- VINNOVA, Swedish Agency for Innovation Systems
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To develop efficient and reliable methods for prediction of serum protein binding of drug leads, the kinetic characteristics for the interactions between selected compounds and human serum albumin and alpha(1)-acid glycoprotein have been explored using a surface plasmon resonance biosensor. Conventional methods for quantification of interactions (i.e., using rate constants or affinities determined on the basis of a reasonable mechanistic model) were applicable for only a few of the compounds. The affinity of a primary interaction and the contribution of lower affinity secondary interactions could be estimated for some compounds, but the affinity of many compounds could not be quantified by either of these methods. To have a quantification method that could be used for all compounds, independent of affinity and complexity of interaction mechanisms, the concept of binding efficiency, analogous to catalytic efficiency used for enzymes, was developed. It allowed the quantification of the binding of compounds interacting with weak affinity and for which saturation is not reached within a concentration range where the compound is soluble or when the influence of interactions with secondary sites makes interpretations difficult. In addition, compounds with large fractional binding can be identified by this strategy and simply quantified relative to reference compounds. This approach will enable ranking and identification of structure-activity relationships of compounds with respect to their serum protein binding profile. (C) 2010 Elsevier Inc. All rights reserved.
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