Pharmacophore-based methods

3D structure [10]. Both fingerprint and pharmacophore models are often used to rapidly screen large compound collections to identify novel potential hits [11]. 

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Xue L, Stahura FL, Godden JW, Bajorath J. Mini-fingerprints detect similar activity of receptor ligands previously recognized only by three-dimensional pharmacophore-based methods. J Chem Inf Comp Sci 2001 41 394-401. 

In this section, a number of case studies (Table 5) in which different types of VS methods are combined into a hybrid workflow. Often these combine a fast, ligand or pharmacophore-based method with a later docking method. The latter is useful at the inspection stage as it allows the molecule to be reviewed within the context of the protein binding site. A poor binding pose can be an indicator of a poor fit. Furthermore, possible interactions outside the scope of the molecules used to train the ligand-based method can be identified. 

In contrast to essentially all 2D approaches, most but not all 3D methods have a distinct advantage, in that they account for stereochemistry in a natural way (e.g., 3-point pharmacophore-based methods cannot describe the stereochemistry about asymmetric carbon atoms). Although important, incorporation of information on protonation and tautomeric states is at best sporadically treated in similarity methods due primarily to the difficulty of reliably estimating these states. The papers by Nettles et al. [112] and Oellien et al. [113] provide a nice overview of many of the issues confronting both 2D- and 3D-based methods, and the book by Martin [114] provides discussions and additional references on the role of tautomeric structures in chemical informatics and modeling. 

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