HipHop

Clement OO, Mehl AT. HipHop pharmacophores based on multiple common-feature alignments. In Gtiner OF, editor. Pharmacophore perception, development and use in drug design. La Jolla International University Line, 2000. p. 69-84. 

Clement, O.O. and Mehl, A.T. (2000) HipHop pharmacophores based on multiple common-feature alignments, in Pharmacophore Perception, Development, and Use in Drug Design (ed. O.F. Giiner), International University Line, La Jolla, CA, pp.69-84. 

Unfortunately, FfipFfop and HypoGen cannot process the large training sets of the size used for QSAR model building. The set of 29 most potent Cox2 inhibitors has been submitted to HipHop and the best of the resulting hypotheses has been qualitatively compared to the overlay-based QSAR model hypothesis. 

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 —CF3 substituent matches the hydrophobic feature next to the central 5-membered ring hypothesized by both ComPharm and HipHop - both approaches agreeing that the trifluoromethyl group actually is a hydrophobe. The interaction map, however, shows a more subtle picture while the —CF3 group is partly surrounded by hydrophobes, it also forms a close contact to Arg 120, a cation and hydrogen bond donor. 

The HipHop algorithm [71] attempts to produce an alignment of compounds expressing certain activity against a particular target and by superposition of di-... 

HypoGen consists of three phases constructive, subtractive and optimization. Generally, the constructive phase is similar to the proceeding of the HipHop algorithm. The training set is divided into two subsets, active and inactive ... 

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

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). 

Fig. 14.3 A. A preliminary HipHop pharmacophore for the breast cancer resistance protein derived for seven inhibitors (Maliepaard et al., 2001) showing SN-38 (yellow) and gleevec (green). B. Gleevec mapped to the...

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

Objective Find common feature configurations amongst a set of active molecules. Algorithm HipHop uses a pruned exhaustive search method. Starting with simple two-feature pharmacophores, the program tries to add one extra common feature at a time until no larger common pharmacophore configuration exists [10]. Combinations that cannot be completed to reach a minimum number of features are not further explored. 

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. 

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. 

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

---