Pharmacophore libraries

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-... 

Fig. 1.10. Statine pharmacophore library targeting aspartic acid proteases (reprinted ( adapted or in part ) with permission from Journal of the American Chemical Society. Copyright 2001 American Chemical Society).

A variation of the pharmacophore library was seen in an approach used to determine CD4+ T cell epitopes.31 In a 14-mer peptide, the researchers keep residues in positions 1, 4, and 6 constant since they functioned as anchor positions for binding receptor, and proceeded to vary the other residues in the peptide. This allowed the use of a shorter synthetic route compared to one that would be needed if all positions were to be varied. Limiting the size of the library allowed the authors to obtain better assays. By doing a partial release of the peptides, the authors were able to find the final peptide that represented the epitope of the T cell receptor. In another example, the epitope to inhibit stimulation of the thyrotropin receptor also was found via combinatorial libraries.32 Since the synthesis of a totally random hexapeptide library was deemed impractical, the authors opted to hold one position constant while the other five residues were randomized. This method was repeated for each residue in the peptide. The residues that were determined to be the most active were used as a basis for a second-generation library. The only limitation of the library was not the quantity of product synthesized, but to properly pinpoint the peptides in an assay. 

Parallel synthesis and screening of bioactive pharmacophore libraries... 

Kingston DGI, Newman DJ. The search for novel dmg leads for predominately antimmor therapies by utilizing mother nature s pharmacophoric libraries. Curr. Opin. Drug Disc. Develop. 2005 8 207-227. 

Another concept utilizing antisense are dual pharmacophore libraries, in which two fragments, each on its own single-strand DNA tag, are spatially aligned via antisense regions close to the fragments [161]. 

Heterocyclic compounds are of great interest to the pharmaceutical industry, as they make up most of the known pharmacophores. As a result, a number of libraries of various heterocycles have been prepared using polymer-supported reagents. While an exhaustive list of all the heterocychc cores that have been prepared using PSRs is beyond the scope of this chapter, some selected examples are depicted in Scheme 3. 

Davies K. Using pharmacophore diversity to select molecules to test from commercial catalogues. In Chaiken IM and Janda KD, editors. Molecular diversity and combinatorial chemistry. Libraries and drug discovery. Washington DC American Chemical Society, 1996 309-16. 

Mason JS, Morize 1, Menard PR, Cheney DL, Hulme C, Labaudiniere RF. New 4-point pharmacophore method for molecular similarity and diversity applications Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. I Med Chem 1999 42 3251-64. 

Beno BR, Mason JS. The design of combinatorial libraries using properties and 3D pharmacophore fingerprints. Drug Discov Today 2001 6(5) 251-8. 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Lee, M.L. Schneider, G. (2001) Scaffold Architecture and Pharmacophoric Properties of Natural Products and Trade Drugs Application in the Design of Natural Product-Based Combinatorial Libraries. Journal of Combinatorial Chemistry, 3, 284-289. 

McGregor, M. J., Muskal, S. M. Pharmacophore fingerprinting. 2. Application to primary library design. 

---