Agentes antitumorais inibidores da angiogênese: modelos farmacofóricos para inibidores da integrina ;anb;3

Cancer is one of the leading causes of death. Angiogenesis, the growth of new blood vessels, is essential for tumor development and spreading. Integrins are a family of surface receptors that are involved in angiogenesis. The ;anb;3 integrin plays an important role in tumor angiogenesis. ;anb;3 inhibitors have direct effects to prevent tumor metastases, growth and angiogenesis. In vitro screening of cyclic peptide libraries led to highly active and ;anb;3-selective compounds. Non-peptidic ;anb;3 antagonists were also designed and synthesized. The crystal structure of the ;anb;3 integrin in complex with RGD ligant allowed structure-based rational design of ligands and validation of pharmacophore model to ;anb;3 antagonists.O câncer é, atualmente, uma das principais causas de morte no mundo. A angiogênese, formação de novos vasos capilares a partir de células endoteliais, é essencial para vários processos fisiopatológicos, tais como o desenvolvimento e a disseminação dos tumores. As integrinas são uma família de receptores de superfície que estão envolvidos na angiogênese, na qual a integrina ;anb;3 exerce papel importante. Os antagonistas da integrina ;anb;3 têm efeitos diretos na prevenção do crescimento, angiogênese e metástase tumorais. A avaliação in vitro frente à integrina ;anb;3 de coleções de ciclopeptídeos levou a compostos muito ativos e seletivos. Antagonistas não-peptídicos da integrina ;anb;3 também foram planejados e sintetizados. A partir da determinação da estrutura tridimensional da integrina ;anb;3 complexada com um inibidor, tornou-se possível o planejamento racional de ligantes com alta afinidade. Além disto, estes estudos permitiram a validação e o refinamento de modelo farmacofórico para os inibidores da integrina ;anb;3

Molecular modeling study of complexes between ferriprotoporphyrin IX and antimalarial 4-quinolinecarbinolamines: a proposal of pharmacophore

Quinine and quinidine are well-known 4-quinolinecarbinolamines that exhibit antimalarial activity, but, in contrast, their epimers 9-epiquinine and 9-epiquinidine are almost inactive. Literature data are conflicting in describing the 4-quinolinecarbinolamine interaction mode with the molecular target, the ferriprotoporphyrin IX [Fe(III)PPIX]. In the present paper, a pharmacophore is proposed based on the binding of the non-aromatic nitrogen to the iron atom. The 4-quinolinecarbinolamine antimalarials were superimposed on the pharmacophore under consideration and complexes with Fe(III)PPIX were constructed. Conformational analyses of the complexes were performed applying the MM+ molecular mechanics method. The analysis of the complexes showed that the proposed ligand mode is possible although it does not explain the activity differences between epimers. A discussion of the structural aspects is also provided.