RESUMO
We present a general approach which allows automatic identification of sub-structures in proteins that resemble given three-dimensional templates. This paper documents its success with non-peptide templates such as beta-turn mimetics. We considered well-tested turn-mimetics such as the bicyclic turned dipeptide (BTD), spiro lactam (Spiro) and the 2,5-disubstituded tetrahydrofuran (THF), a new furan-derivative which was recently developed and characterized. The detected geometric similarity between the templates and the protein patches corresponds to r.m.s.-values of 0.3 A for more than 80% of the constituting atoms, which is typical for active site comparisons of homologous proteins. This fast automatic procedure might be of biomedical value for finding special mimicking leads for particular protein sub-structures as well as for template-assembled synthetic protein (TASP) design.
Assuntos
Desenho de Fármacos , Mimetismo Molecular , Proteínas/química , Simulação por Computador , Bases de Dados de Proteínas , Modelos Moleculares , Estrutura Molecular , Biblioteca de Peptídeos , Ligação ProteicaRESUMO
The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).