Exploiting similarity between highly flexible and dissimilar molecular structures

Abstract

There are many examples of chemically unrelated and apparently dissimilar molecules that bind to a common site at a receptor and elicit the same pharmacological response. Ideally, these drug-receptor interactions would be examined using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy to provide a detailed atomic description of the interaction. This information could then be used as the basis for the direct design of ligands to fit this site. However, despite the dramatic increase in the number of crystal structures of enzyme-ligand complexes in recent years, it is still the case that there are no crystal data for the vast majority of potential drug molecules in their sites. Membrane-bound receptors are a notable example of the problem since they are often pharmacological and therapeutic targets, and have provided no crystal structures to date. In this type of situation, a less direct approach must be used; an obvious tactic is to compare a series of ligands known to bind to the site and attempt to determine their common features and potential pharmacophores. If the molecules can be superposed in three-dimensional (3D) space, their properties can be studied using 3D quantitative structure-activity relationships (QSAR) using procedures such as CoMFA (Cramer et al. 1988; see also Chapter 12). This, in turn, may allow the design of novel molecules taht incorporate some or all of the common features and that should therefore be capable of binding to the same receptor site.