Pharmacophore Modeling

Pharmacophores and pharmacophore elements are central concepts in medicinal chemistry. The idea behind these concepts comes from the common observation that variations of some parts of the molecular structure of a compound drastically influence the activity at a target receptor, whereas variations of other parts only cause minor activity changes.

A "pharmacophore element" is traditionally defined as an atom or a group of atoms (a functional group) common for active compounds at the receptor in question and essential for the activity of the compounds. However, the concept of a pharmacophore element may fruitfully be extended to include representations of interactions of ligand functional groups with receptor sites. The "pharmacophore"

A set of active »A compounds

A set of active »A compounds


Conformational analysis



Identify repulsive steric interaction

Proposed bioactive conformations

Identify repulsive steric interaction

FIGURE 3.1 Basic principles of the development of a 3D-pharmacophore model.

is a collection of pharmacophore elements and the concept of "3D-pharmacophore" may be used when the relative spatial positions of the pharmacophore elements are included in the analysis. Thus, a 3D-pharmacophore consists of a specific 3D-arrangement of pharmacophore elements.

The basic principles of the development of a 3D-pharmacophore model are illustrated in Figure 3.1. On the basis of conformational analysis of a set of active molecules with pharmacophore elements A, B, and C, a low energy conformation of each molecule is selected for which the pharmacophore elements of the molecules overlap in space as shown in the figure. Conformational energies in ligand-protein binding are discussed in more detail in Chapter 1. The selected conformations are the putative bioactive conformations of the molecules and the overlapping pharmacophore elements and their spatial positions make up the 3D-pharmacophore.

The development of a 3D-pharmacophore model requires that a number of active compounds and their affinities for the receptor in question are available. The necessary number of compounds depends mainly on the conformational flexibility of the ligands. In the case of highly flexible molecules, the development of a pharmacophore model generally requires a larger number of compounds compared to the case in which the compounds are less flexible.

In addition to active compounds, it is highly useful that a number of inactive compounds also are available. These may, as will be demonstrated in the following text, fruitfully be used to identify regions of sterically repulsive ligand-receptor interactions and thus provide an estimate of the dimensions of the binding cavity.

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