HIPHOP pharmacophore model

Box 2. Ligand-based automated pharmacophore model generators Catalyst HipHop [9]... 

Lu et u/. screened a prefiltered set of 11000 compounds from the NCI database with a pharmacophore model based on the crystal structure of murine double minute 2 (MDM2) oncoprotein in complex with the p53 tumor suppressor and several non-peptide small inhibitors. The remaining compounds were docked, scored, and 67 compounds were selected for testing, ten of which were active in a competitive binding assay. Similarly, Yu et used a Catalyst HipHop model combined with the molecular shape of an experimental X-ray... 

Fig. 5.4 Comparative display of a catalyst-HipHop hypothesis and the pharmacophore field descriptors selected by the minimalist ComPharm overlay-based model. ComPharm key features are pinpointed by arrows, while HipHop feature spheres stand for hydrophobes (light blue) and hydrogen bond acceptors (green).

The BCRP is an ABC transporter similar to P-gp whose expression results in resistance to anticancer therapeutics and may limit intestinal absorption of drugs. However, there have been limited studies to elucidate the selectivities of dmgs for P-gp and BCRP (Brooks et al. 2004). We used a published dataset of seven topoisomerase inhibitors (Maliepaard et al. 2001) to construct a HipHop model for BCRP. We then mapped the potent tyrosine kinase inhibitor Gleevec to this pharmacophore as this compound has been suggested experimentally in conflicting studies as both a substrate and inhibitor of BCRP (Burger et al. 2004 Houghton et al. 2004). 

Do I like the proposed hypothesis Although very subjective, this approach tends to counter-balance the inherent imperfections of automated methods. Programs such as DISCO and HipHop will provide multiple output models among which the expert has to choose the most acceptable. The eye is often the first and best critic for the pharmacophore hypotheses. 

Figure 5.9 Generation of models for CB2 ligands. The HipHop algorithm of DS CATALYST performed a 3 D alignment ofthe five training set compounds AM1241, GW405 833, HU-308, JWH-133, and JWH-267 and identified common pharmacophoric patterns. This resulted in the...

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