Pharmacophores defined

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. 

Figure 5 Five merged P-gp inhibition Catalyst pharmacophores defining areas of hydrophobicity = solid circles aromatic rings = bold circle, and hydrogen-bond acceptors = square.

A variant of distance geometry called ensemble distance geometry [Sheridan et al. 1986] can be used to simultaneously derive a set of conformations with a previously defined set of pharmacophoric groups overlaid. Ensemble distance geometry uses the same steps as... 

This rarity value is equated with the fraction of hits that would be returned by searching large database of diverse molecules with the full pharmacophore (all K features) or thi subset (with K—1 features) as appropriate. Labelling this fraction of hits as p(x) we nov define q x) as the fraction of the M active molecules (i.e. the molecules originally suppliet as input to the procedure) which match each of the K + possible classes. The overal configuration is scored using ... 

Figure 13.2 A typical Catalyst pharmacophore, where different colors indicate different chemical features and the spheres define tolerance spaces that each chemical feature would be allowed to occupy. See color plate.

By experiments performed as discussed here, the reversible inhibition modality of each lead compound, representing a distinct pharmacophore or chemical structural class, can be defined and the dissociation constant (A) or aK<) can be determined from the data fitting to Equations (3.1) through (3.6). As lead analogues are produced within a structural series, one can generally assume that the inhibiton modality will be the same as that of the founder molecule (i.e., the lead) of that structural series. This assumption simplifies the determination of dissociation constants for other series molecules, as described below. However, this assumption must be... 

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