Pharmacophore Mapping Using Constrained Systematic Search

The constrained systematic search approach has its origins in the development of efficient algorithms for systematically exploring conformational space [Motoc et al. 1986]. As explained in the discussion on systematic conformational search methods, such procedures have an exponential dependence on the number of rotatable bonds in the molecule. By making use of tree-pruning methods (described earlier) to eliminate unfavourable, high-energy conformations the efficiency of these algorithms can be considerably improved. The constrained systematic search procedure for pharmacophore generation further improves the efficiency by deriving additional constraints on the torsional angles.

The first part of the procedure is to identify the pharmacophoric groups in each molecule that will be overlaid in the final pharmacophore. The most rigid molecule is then taken and its conformational space explored. During the conformational search the distances between all pairs of the selected pharmacophoric groups are recorded. The second most rigid molecule is then taken, and using the d2

r

r

iJ

di d

Figure 2-9. As successive molecules are considered in the constrained systematic search procedure so the distance constraints between pharmacophoric features become more restricted. Thus the figure on the left shows the distances permitted to the first molecule; these regions may be further restricted after analysis of the second molecule. (Adapted from Leach 2001.)

inter-pharmacophore distance ranges derived from the first molecule, constraints on the values permitted to each of its torsion angles are derived. Thus the only torsion angle values explored for the rotatable bonds in the second molecule are those that may permit it to match the pharmacophore distances found for the first molecule. As more and more molecules are considered so the distance ranges become more and more restricted (see Figure 2-9). When the more flexible compounds are considered the expectation is that only very limited ranges are possible on each of its torsion angles, making the search very efficient.

The classic application of the constrained systematic search procedure is to the discovery of 3D pharmacophores for the inhibition of Angiotensin Converting Enzyme (ACE), an enzyme involved in the regulation of blood pressure [Dammkoehler et al. 1989]. Typical inhibitors of ACE, some of which are shown in Figure 2-10, contain a zinc-binding group such as a thiol or a carboxylic acid, a terminal carboxylic acid group that interacts with a basic residue in the protein and an amido carbonyl group which acts as a hydrogen bond acceptor. The constrained systematic search method derives distance ranges between these features, accessible to all of the ACE inhibitors in a low-energy conformation. Two pharmacophores result from this analysis. Note that one of the pharmacophoric features is an extended point, corresponding to the presumed location of the zinc atom in the protein. The constrained systematic search was three orders of magnitude faster than an equivalent systematic search on each individual molecule, illustrating the advantage of using prior information to restrict the conformational search space.

A drawback of the constrained systematic search approach is that it is necessary to specify manually beforehand which pharmacophoric groups in each molecule are involved in interactions with the receptor, and the correspondences

O COOH

N COOH

Figure 2-10. Some typical ACE inhibitors together with the features and the five distances used to define the 3D pharmacophores as discovered by the constrained systematic search method [Dammkoehler et al. 1989]. The two pharmacophores found correspond to different values of the distances ¿1 —¿5. Du indicates the presumed location of the zinc atom in the enzyme (the extended point).

N COOH

Figure 2-10. Some typical ACE inhibitors together with the features and the five distances used to define the 3D pharmacophores as discovered by the constrained systematic search method [Dammkoehler et al. 1989]. The two pharmacophores found correspond to different values of the distances ¿1 —¿5. Du indicates the presumed location of the zinc atom in the enzyme (the extended point).

between these groups. It may be difficult to do this when there are many potential pharmacophores in the molecules, giving rise to many possible matches. The three remaining methods that we will discuss do not require the user to specify such correspondences; rather the algorithms determine them automatically.

Fitness Resolution Fortress

Fitness Resolution Fortress

Learning About Fitness Resolution Fortress Can Have Amazing Benefits For Your Life And Success! Start Planning To Have Excellent Health And Fitness Today!

Get My Free Ebook


Post a comment