Pharmacophore Building

Our primary interest being the search for new high-affinity ligands, we decided to build a pharmacophore model for antagonists of the cq-AR and in the first step did not consider any selectivity criteria between the cq-AR subtypes and between cq-AR and other GPCR. 

As a result, 10 additional compounds were added to obtain the final training set constituted by a total of 24 structures. Biological data associated with these compounds, expressed as Kit ranged between 0.21 nM, found for compound 5, and 2396 nM, found for compound 7 (Table 12.1). We assumed that all these compounds were acting through the same mechanism of action at the same binding site. 

Compounds and their conformational models were imported to Catalyst and subjected to the HypoGen routine to build chemical feature-based pharmacophore models using hydrogen bond acceptor lipid (HBA), hydrogen bond donor (HBD), positive ionizable (PI), ring aromatic (RA) and hydrophobic  

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The pharmacophore build-up procedure is similar to that in Catalyst HipHop. Two-point pharmacophores characterized by the two features and a binned dis-... 

Scaffold proposals were collected and reviewed according to privileged ion channel motifs, chemical feasibility, and fit to our multiple pharmacophores. Building block selection, virtual library design, and filtering yielded small virtual libraries suitable for automated solution-phase synthesis. All synthesized compounds were finally purified and characterized prior to addition to our focused library. 

These pharmacophore techniques are different in format from the traditional pharmacophore definitions. They can not be easily visualized and mapped to the molecular structures rather, they are encoded as keys or topological/topographical descriptors. Nonetheless, they capture the same idea as the classic pharmacophore concept. Furthermore, this formalism is quite useful in building quantitative predictive models that can be used to classify and predict biological activities. 

Attempts to build predictive models based on common pharmacophoric elements have had some modest success. In the most general sense, a basic nitrogen atom which is substituted by aromatic or otherwise hydrophobic groups is a clearly problematic motif [73,74]. However, there are many compounds which interact with hERG which do not contain these features, and newer pharmacophore models have been proposed... 

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