Protein binding model

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. 

Liu, J., Yang, L., Li, Y, Pan, D. and Hopfinger, A.J. (2006) Constructing plasma protein binding model based on a combination of cluster analysis and 4D-fingerprint molecular similarity analyses. Bioorg. Med. Chem., 14, 611-621. 

Figure 12 Comparison of the parabolic Hansch model (left curve) and Franke s protein binding model (right curve). Log P, is the lipophilicity limit, where steric hindrance or other unfavorable interactions cause a change of the linear lipophilicity-activity relationship to a parabola (reproduced from Figure 9 of ref. [175] with permission from Birkhauser Verlag AG, Basel, Switzerland).

The protein-binding model of Franke yields a complex function between the logarithm of the biological activity and some suitable hydrophobic parameter consisting of a linear part that passes into a parabola if steric hindrance occurs (Franke and Schmidt, 1973). 

The binding model, suggested by Brian Matthews, is shown schematically in (a) with connected circles for the Ca positions, (b) A schematic diagram of the Cro dimer with different colors for the two subunits, (c) A schematic space-filling model of the dimer of Cro bound to a bent B-DNA molecule. The sugar-phosphate backbone of DNA is orange, and the bases ate yellow. Protein atoms are colored red, blue, green, and white, [(a) Adapted from D. Ohlendorf et al., /. Mol. Evol. 19 109-114, 1983. (c) Courtesy of Brian Matthews.]... 

These CD studies confirmed the binding stoichiometries of our aPNA-DNA complexes and provided further support for our binding model. Comparisons between the CD spectra of the individual components and the aPNA DNA complex suggest a template effect (not unhke that observed with certain DNA-binding proteins) where the components induce mutual conformational changes upon their interaction with each other. 

McMahon, M. T., deDios, A. D, Godbout, N., Salzmann, R., Laws, D. D., Le, H., Havlin, R. H., Oldfield, E., 1998, An Experimental and Quantum Chemical Investigation of CO Binding to Heme Proteins and Model Systems A Unified Model Based on 13C, 170 and 57Fe Nuclear Magnetic Resonance and 57Fe Mossbauer and Infrared Spectroscopies , J. Am. Chem. Soc., 120, 4784. 

Fig. 4 HLM Clint, free vs clogD. HLM Clint, app corrected for microsomal protein binding using a computational model for microsomal binding. Open squares and filled triangles represent the same chemical series as in Fig. 3 (series A and B, respectively)...

During the characterization process, hits are typically tested for kinetic solubility and permeability in a model of passive diffusion such as PAMPA [22]. As new compounds are synthesized, additional parameters also need to be considered, such as pZa, chemical and plasma stability, and protein binding. Calculated properties such as MW, clogP, and PSA should also be tracked. 

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