ACE pharmacophore

Fig. 12.10 Two ACE pharmacophores identified by the constrained systematic search [Dammkoehler et al. 1989],...

Figure 2 ACE pharmacophore of Mayer et al. All distances are in angstrom. Du refers to a dummy atom projected from the sulfur atom. Tolerances on these constraints were not given.

To derive an ACE pharmacophore, four points were defined for each molecule. The derivation of these four points for captopril is shown in Figure 12.8. Five distances (also shown in Figure 12.8) were defined between these four points. Note that one of the points corresponds to the presumed location of the enzyme s zinc atom. The number of rotatable bonds in each inhibitor varied between 3 and 9 and the molecules were considered in order of increasing number of rotatable bonds. The entire conformational space was explored for the first (most... 

Mercaptoacyl pharmacophore library. Zinc metalloproteases are inhibited by small molecules that contain mercaptans (thiols -CH2SH), carboxylic acids (-CO2H), and hydroxamic acids (-CONHOH). These functional groups chelate the active-site metal disrupting normal enzyme function. The angiotensinconverting enzyme (ACE) inhibitor Captopril is an example of a thiol-based metalloprotease inhibitor. Thiols, carboxylic acids, and hydroxamic acids are consequently affirmed pharmacophores for this protease family. A historical example of a pharmacophore-... 

The authors illustrated the approach by using two datasets 1650 MAO inhibitors from Abbott and 114 ACE inhibitors. The pharmacophores identified by the program match some known SAR, especially the multiple mechanism of action in the MAO series [104]. 

Fig. 4.5 Examples of different scaffolds for ACE inhibitors having three pharmacophoric features separated by variable linker regions.

Figure 1.13 A suggestive structural correspondence between the ACE inhibitor Quinalapril (left) and bradykinin was used to design novel B2 receptor antagonists, one of them shown on the right [63], For details of this convergent pharmacophore strategy, see the text.

Figure 9.3. MACCS— the Molecular ACCess System—an early structure indexing system. This program originally used fixed menus for searching, registration, and reporting. Later versions allowed users to customize the menus. The figure shows the result of a 3D pharmacophore search for ACE inhibitors. Out of a database of 115,000 structures, 21 fit the 2D and 3D requirements of the search query. The user could typically browse the "hits" from the search, save the list of structures to a list file, and output the structures to a structure-data file (SDFile). The MACCS database was a proprietary flat database system in which data of a given type, say, formula, was stored in a given file, indexed by the compound ID number.

A rational approach toward one of the earhest ACE/ NEP dual inhibitors, dipeptide 18, demonstrates how a good understanding of the pharmacophore requirements for... 

This approach has been used successfully in the design of potent, selective, and stereospecific 5-HTia compounds.i A refinement of this method, which allows comparison of varied structures because it does not assume a common molecular framework, has been used to determine the pharmacophore for inhibiting angiotensin-converting enzyme (ACE). 

Figure 1 Representative pharmacophore queries (a) simple thromboxane synthetase inhibitor, (b) CNS agent, and (c) optimized receptor-based ACE inhibitor query derived from bound inhibitor of carboxypeptidase A...

---