Pharmacophores distance ranges

In addition, researchers can survey the surface and clefts of a macromolecule for potential receptor sites based on Hgand distance ranges "use the common distance range of the superimposed atoms" (116) to faciHtate the development of a "pharmacophore" or critical contact assembly besides the Hgand... 

For example, let us consider a two-center pharmacophore that has a distance of 4.85 A between the centers. Applying a distance tolerance of 0.25 A gives a range of possible distances between 4.6 and 5.1 A. The default distance bins that cover this range are 4.0-5.0 and 5.0-6.0 A 80% of the distance range lies within the 4.0-5.0 A bin and 20% within the 5.0-6.0 A bin. Hence this two-center pharmacophore would generate two fractional pharmacophores, one with a count of 0.8 and the other with a count of 0.2. 

Using 4-point pharmacophores enables chirality to be handled and adds some elements of volume/shape linked to electronic properties, increasing separation in similarity and diversity studies. There is a large increase in the number of potential pharmacophores that need to be considered. For example, using six possible feature types for each point, and 10 distance ranges (bins) for each feature-feature distance, the number of potential pharmacophores increases from 33 000 for 3-point pharmacophores to 9.7 million for 4-point pharmacophores [14—16]. Reducing the number of distance bins to seven reduces these numbers to 9000 and 2.3 million respectively. 

Figure 5.7. Comparisons of the 3D four-point pharmacophore fingerprints exhibited by several sets [MDDR database of 62,000 biologically active compounds, a corporate registry database of 100,000 compormds used for screening, 100,000 compounds from combinatorial libraries (from a four-com-poilent Ugi condensation reaction), and 14,000 compound random subsets (MDDR, corporate) or indlividual libraries]. The four-point potential pharmacophores were calculated using 10 distance range bins and the standard six pharmacophore features.

Figure 6.22. Pharmacophore proposed for identifying DAT inhibitors. The pharmacophore was obtained based on two known DAT inhibitors, R-cocaine and WIN-35065-2. Distance ranges between pharmacophore points were obtained through systematic search of all possible conformations that the two compounds may adopt when bound to DAT.

After PPP type assignments, all interatomic distances are calculated and represented by the bins into whose distance ranges they fall. Six distances are needed to describe each combination of four PPP types. Seven or 10 nonuniform distance ranges (Table S23) were proposed to calculate 4-PPP keys since they were found to be the best trade-off among differentiation, resolution, and manageable descriptor size (e.g., around 5.6 million pharmacophore/molecule with 7 ranges and 24.4 million with 10 ranges). 

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