Ligand-Based Drug Design - Drug Design and Discovery - page 44

of this chapter is to introduce and discuss some major methods used for ligand-based drug design
and to exemplify the use of these methods by a case study in which the discovery of novel ligands
for the benzodiazepine (BZD) site of the g-aminobutyric acid type A (GABA A ) receptor have been
successfully accomplished. For details of this case study the reader is referred to the references in
the Further Readings section.
The most important and powerful method in ligand-based drug design is “pharmacophore mod-
eling,” which is used to develop a pharmacophore model describing the interactions between ligands
and the target receptor from the ligand point of view. We will discuss and illustrate how a well-
developed pharmacophore model can be used to search databases for new compounds, which i t the
model and to optimize identii ed compounds by a pharmacophore-guided procedure.
A pharmacophore model does not give a quantitative prediction of receptor afi nities. The main
use of such a model is restricted to the prediction of candidate ligands as active or inactive. Such
a classii cation may be fruitfully used in the selection of new molecules to be synthesized and
pharmacologically tested in a drug discovery project. However, a pharmacophore model may addi-
tionally be used as a starting point for 3D quantitative structure-activity relationships (3D-QSAR)
analysis. The 3D-QSAR combines pharmacophore models, molecular interaction i elds and statis-
tical chemometrics methods to give quantitative predictions of receptor afi nities and in addition
guidelines for ligand optimization. This methodology will be discussed in the last part of this
chapter.
3.2 THE BENZODIAZEPINE SITE OF GABA A RECEPTORS
GABA A receptors are transmembrane proteins that are assembled from subunits into a pentameric
structure forming an ion-channel through which the inl ux of chloride ions is regulated. In addition
to the binding site for the endogenous agonist GABA, the GABA A receptors have binding sites for
compounds that allosterically modify the chloride channel gating of GABA. The most well-known
class of such compounds is the BZDs and the binding site for this class of compounds has been
named the BZD site. The pharmacological effects of the BZDs (anxiolytic, anticonvulsant, muscle
relaxant, and sedative-hypnotic) make them the most important GABA A receptor-modulating drugs
in clinical use.
In addition to the BZD class of compounds, it has been shown that many other classes of com-
pounds bind to the BZD site and a pharmacophore model including several classes of compounds
have been developed (see Further Readings). In addition, naturally occurring and synthetic deriva-
tives of l avones have also been shown to bind to the BZD site. The l avone class of compounds is
the starting point for the case study described in this chapter.
At present there is no experimentally determined 3D structure for any of the subtypes of the
GABA A receptor. Thus, in the computational part of a drug discovery project dealing with this
class of receptors, the use of ligand-based drug design methods is the only alternative. For a more
detailed discussion on GABA A receptors and their ligands, see Chapter 15 and the use of GABA
ligands as hypnotics is discussed in Chapter 20.
3.3 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 inl uence the activity at a target receptor, whereas
variations of other parts only cause minor activity changes.
A “pharmacophore element” is traditionally dei ned 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 liga nd functional groups with receptor sites. T he “pha r macophore”