Humans plasma protein binding

Lobell M and Sivarajah V. In silico prediction of aqueous solubility, human plasma protein binding and volume of distribution of compounds from calculated pKa and AlogP98 values. Mol Divers 2003 7 69-87. 

Moda, T.L., Montanari, C.A., Andricopulo, A.D. In silico prediction of human plasma protein binding using hologram QSAR. Lett. Drug Des. Discov. 2007, 4, 502-9. 

Figure 5.6 Relationships between percentage human plasma protein binding (hPPB%) and octanol/water logD7 4 [20]. Note the about 2 log units downshift of the sigmoidal relationship for acids as compared to neutrals and basics (copyright Springer-Kluwer).

Tomkinson, N.P. and van de Waterbeemd, H. (2007) QSAR modeling using automatically updating correction libraries application to a human plasma protein binding model. Journal of Chemical Information and Modeling, 47, 2401-2407. 

It is to be expected that the predictive performance of global models will detoriate over time as projects move on and produce new chemotypes not used in the generation of the model. Literature on time-dependent QSAR model behavior is stiU sparse. In a recent investigation this effect was shown for a human plasma protein binding (hPPB) model.A solution to this behavior is the use of correction libraries (see Section in.B.4.) and/or to update (rebuild) the model regularly. " An automated approach to this problem has been published and it is expected that this technology (autoQSAR) will become more widespread in the future. " ... 

Rodgers, S. L., Davis, A. M., van de Waterbeemd, H. Time-series QSAR analysis of human plasma protein binding data. QSAR Comb. Sci. 2007,26,511-521. 

The most widely used technique for the evaluation of hERG channel interaction is the voltage clamp. A detailed description of the experimental setup has been described elsewhere [119]. The hERG interaction is measured and reported as the % inhibition of the hERG current compared to the vehicle control at various concentrations of the NCE. The concentration that inhibits 50% (IC50) is calculated, whenever possible. The concentrations of NCE used in the assay are carefully selected based on the expected maximum plasma concentration (Cmax) at the pharmacologically active dose (usually based on studies in animal models) and the human plasma protein binding for the NCE. 

The temporal predictivity of 3 endpoints (logDy 4, solubility in pH 7.4 buffer and human plasma protein binding) with 3 different statistical learners partial... 

Figure 9.3 Initial model predictivity of cumulative monthly test sets. Human plasma protein binding (top), and lipophilicity log D7.4 (bottom).

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