Ligand-based methods

Given the relative simplicity of ligand-based methods, it is interesting to note that in only comparatively few published reports of VS successes do the authors rely primarily on ligand-based methods. Of these studies, most appear to combine an interest in a given target with an interest in providing proof-of-concept for some extension of chemoinformatic theory. 

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. 

Include a 3D ligand-based method. In our internal efforts across two companies, we arrived at the same conclusion as the Merck researchers [106] that a 3D similarity method appears to offer a good balance between effort expended and the number and novelty of hits generated. 

Sippl, W., Holtje, H.-D. Structure-based 3D-QSAR - Merging the Accuracy of Structure-based Alignments with the Computational Efficiency of Ligand-based Methods. /. Mol. Struct. (Theo-chem) 2000, 503, 31-50. 

We have presented a netv procedure, called PathFinder, aimed at encoding the GRID molecular interaction fields into invariant shape-descriptors, suitable for similarity and complementarity issues. Shape similarity is the underlying foundation of ligand-based methods tvhile shape complementarity is the basis of many receptor-based designs. 

CYP isoform specificity predicts the subtype responsible for the main route of metabolism. This type of study started from the work by Manga et al. (52), in which the isoform specificity for CYP3A4, CYP2D6, and CYP2C9 substrates was investigated. Terfloth et al. (53) reported a similar study on the same dataset using ligand-based methods, and the accuracy of prediction was improved substantially. 

Sippl W. Receptor-based 3D QSAR analysis of estrogen receptor ligands— Merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods. J Comput Aided Mol Des 2000 14 559-72. 

Several methods have been used in recent years to evaluate profiling data. We will introduce protocols that describe the most common methods and their underlying theory. In particular, this review focuses on ligand-based methods and powerful, modern statistical approaches developed in recent years in the cheminfor-matics field. 

Hristozov, D., Oprea, TL, Gasteiger, J. Virtual screening applications A study of ligand-based methods and different structure representations in four different scenarios. J. Comput.-Aided Mol. Des. 2007,21,617-40. 

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