12 - substrates pharmacophores

Figure 20.2 Pharmacophore models for P-gp inhibition. A. P-gp inhibition pharmacophore aligned with the potent inhibitor LY335979. B. P-gp substrate pharmacophore aligned with verapamil. C. P-gp inhibition pharmacophore 2 aligned with LY335979. Green indicates H-bond acceptor feature, and cyan indicates hydrophobic feature. See color plate.

For example, one might design a GPCR target class library in which the coverage of GPCR-relevant 3D pharmacophores is maximized, while the coverage of PGP substrate pharmacophores is minimized in the selected products. 

Melet A, Marques-Soares C, Schoch GA, et al. Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry 2004 43 15379-15392. 

Figure 7 The partial similarities between a substrate pharmacophore for CYP3A4 (a), a CYP3A4 autoactivator pharmacophore (b), and a CYP3A4 inhibition pharmacophore (c). Legend H = hydrophobe HBA = hydrogen-bond acceptor HBD = hydrogen-bond donor.

Metabolism is still a barrier to be overcome. Some QSAR, pharmacophore, protein, and rule-based models are available to predict substrates and inhibitors of a specific cytochrome P450 isoenzyme [47-55]. 

Smith PA, Sorich M, McKinnon R, Miners JO. QSAR and pharmacophore modelling approaches for the prediction of UDP-glucuronosyltransferase substrate selectivity and binding. Pharmacologist 2002 44 supplement. 

Smith PA, Sorich MJ, McKinnon RA, Miners JO. Pharmacophore and quantitative structure-activity relationship modeling complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. J Med Chem 2003 46 1617-26. 

Sorich MJ, Miners JO, McKinnon RA, Smith PA. Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity. Mol Pharmacol 2004 65 301-8. 

Penzotti, J. E., Lamb, M. L., Evensen, E., Grootenhuis, P. D., A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein, J. Med. Chem. 2002,... 

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