Ligand-based pharmacophores

Ligand-based pharmacophore Pharmacophore hypotheses generated from known inhibitors... 

Chemical Information, Irvine CA Tripos, Inc. St. Louis MO), similarity searching can be carried out around a well-defined compound class using local descriptors such as atom pairs [46, 47] or topomeric shape [48, 49]. Also, ligand-based pharmacophore searches are able to identify follow-up compounds that are less obvious and more diverse than similarity searches [30, 50-54]. The problem with the latter methods is defining the molecular shape or pharmacophore specifically enough to be useful when there are few hits within a compound class and they cannot be reliably aligned (as is often the case for NMR hits in the absence of detailed structural information). 

In this chapter, we have tried to demonstrate the great diversity of software tools available to the researcher in the area of ligand-based pharmacophore modeling. With the expansion of combinatorial chemistry techniques and the need to manipulate very large amounts of real or virtual chemical data, pharmacophore-... 

A lot of effort has been invested over the past 20 years in the optimization of the different steps of pharmacophore generation molecular editing and 3D representation, combinatorial enumeration, conformational expansion and pharmacophore perception methodologies for small drug-like data sets. However, we note that today there are still some areas with potential for improvement in the field of ligand-based pharmacophore modeling ... 

Schmetzer et al. [27] performed a joint CoMFA and Yak study for 31 cannabi-noids acting on the CB1 receptor. Starting from a ligand-based pharmacophore model, a classical CoMFA investigation was accomplished yielding a correlation... 

Excluded Volume Spheres in Structure-based and Ligand-based Pharmacophore Studies... 

The possibility of adding automatically excluded volume spheres to ligand-based pharmacophores, thus accounting for steric hindrance problems, has re-... 

As shown in the previous section, there have been an impressive number of new approaches and tools appearing in the field of structure- and ligand-based pharmacophore modeling. All of them address slightly different issues and therefore a combination of several methods, as shown in different application examples, can significantly enhance the chances of success. 

Schuster et al developed ligand-based pharmacophore models for 11 (3-hydroxysteroid dehydrogenase (11(3-HSD) inhibitors.By VS they were able to identify inhibitors of this enzyme active in the nanomolar range. 

Kvl.5 potassium channel Aventis in-house (N.R.) DISCO/UNITY Ligand-based pharmacophore 18 5.5 1 (5.6 pM) [45]... 

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]... 

CDK2 Pharmacopeia in-house (117,180) HypoGen/Catalyst Ligand-based pharmacophore 4478 0.8 39 (N.R.) [56]... 

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