Catalyst HipHop

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

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

If one compares Catalyst-HipHop with Catalyst-HypoGen, for instance, it is common to obtain very different models. Since HipHop searches common features amongst active molecules, the output models may have retained features that HypoGen may have discarded as not being relevant to explain activity. The example that we will detail at the end of this chapter is a good illustration of this. It is worth mentioning that this is due to the input dataset and that Catalyst provides solutions to circumvent this. 

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... 

Catalyst/Hiphop was recently used to discover the pharmacophore for mesangial cell (MC) proliferation inhibition [67], This pharmacophore was used in a 3D database search to discover 41 novel inhibitors of MC proliferation. 

Mesangial cell proliferation inhibitors Catalyst/HipHop 7 features N/A... 

A further development of the exhaustive search is Catalyst s HipHop algorithm, just relaxing the GASP requirement that each feature in the... 

Although pharmacophore mapping can be completed manually in simple and straightforward cases, most of the applications require the automated generation of pharmacophore. There are several software suites available for this purpose. HipHop and Hypo-Gen are both featured by the Catalyst package. ... 

Rhinovirus 3C protease WDI (47,660) HipHop/ Catalyst Ligand-based pharmacophore 2467 0.1 3 (N.R.) [48]... 

HIV-1 integrase ChemBridge (150,000) HipHop/Catalyst + GOLD Ligand-based pharmacophore + docking 110 18.0 20 (llpM) [52]... 

DISCO, developed by Yvonne Martin s group at Abbott, and the HipHop [24] module of Catalyst, rely upon pre-calculated conformers. For DISCO these can be generated using a standard modeling package. The Catalyst suite includes a mod-... 

Fully Automated Pharmacophore Discovery Catalyst s HypoGen, DISCO, Catalyst s Hiphop, DANTE... 

DISCO, Hiphop, and DANTE all perform classification. Catalyst s HypoGen predicts activity according to the linear regression performed, using the scoring function described above. 

Befitting the notion that these are fully automated pharmacophore discovery methods, this is minimal, although DISCO, Hiphop, and Catalyst s HypoGen require considerable user intervention to sift through the multiple pharmacophores that emerge. Furthermore, considerable effort is advocated in selecting a representative dataset for HypoGen to avoid nonsensical results. 

All of these methods can easily be coupled to a 3D database search. In particular, the Hiphop and HypoGen pharmacophores can directly be used as input to the Catalyst 3D database search engine. DANTE pharmacophores can be converted into Catalyst 3D search queries, via scripts that convert DANTE output into the Catalyst.chm format. Both DISCO and HypoGen pharmacophores have been used to perform the alignment prior to a CoMFA study. 

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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