Database transporter pharmacophore

Figure 8.1 Schematic of database screening with transporter pharmacophores.

Several papers proposing multiple recognition sites for Pgp have been presented in the past. In this work, the pharmacophoric analysis of the dataset shows that the requirements to interact with Pgp are the same for all 129 compounds. Since in our database we have not included known R-site binders and anthracydines, we cannot say definitively that the pharmacophore found represents one of the binding sites that have been described in the literature. Two of the molecules present in the database, verapamil and dipyridamole, are known to bind in the H-site described by Shapiro and Ling [10]. We also cannot definitely state that the pharmacophore defines any functional site within the transporter. Further work, to try to define the location of the corresponding amino acids in a protein homology model, is in progress. 

QSAR and pharmacophore models for enzymes represent an approach for rapidly screening databases of molecules from companies or vendors that can then be selected and tested in vitro as a rapid approach for finding new inhibitors or substrates. This approach has also been used with transporters (see Chapter 11) [85,86], With numerous crystal structures for mammalian P450s becoming available in recent years (Chapter 17), QSAR models may be used... 

K. M. (2000) Discovery of a novel dopamine transporter inhibitor, 4-hydroy-1 -methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling. Stracture-activity relationships, and behavioral pharmacological studies. J. Med. Chem. 43 351-360. 

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