The importance and specificity of protein associations in cellular events and in the etiology of many pathologic processes make protein-protein interactions (PPI) attractive targets for therapeutic intervention. In cancer, some specific cell surface receptors - e.g. the aVb3, aVb5 and a5b1 integrins and several growth factor receptors – play key roles in tumor angiogenesis, progression and metastasis. The control of tumor cells proliferation is regulated by the activity of these receptors, through the formation of specific PP complexes. Hence, peptidomimetics mimicking the hot spots and the structural features of these protein interfaces represent a promising strategy for obtaining innovative drugs with an optimal pharmacological profile. Our research is aimed at developing an interdisciplinary approach to target integrin-mediated and other cancer-related PPI, based on the interplay between synthetic organic, computational, structural chemistry and biology. The communication will discuss the contribution of various computational techniques to the development of peptidomimetics capable of reproducing the RGD peptide epitope that mediates the interaction between extracellular matrix proteins and integrins in tumor angiogenesis. In particular, the combined use of molecular mechanics, molecular dynamics simulations and docking calculations with available structural information (x-ray, NMR) will be shown in defining the conformation of cyclic peptidomimetics containing rigid diketopiperazine scaffolds, and the ligand-integrin interactions at a molecular level. The different stereochemistry and the different substitution of the scaffold, as well as the RGD or RGD-like recognition sequence, strongly influence the conformations adopted in the free-state and the binding mode of these ligands in the active site of aVb3 and a5b1 integrins. The results will be compared to the results of competitive receptor binding assays, of cell adhesion experiments and of NMR interaction studies of the peptidomimetic ligands with aVb3- and a5b1-integrin rich intact cancer cells.
Targeting protein-protein interactions in cancer with peptidomimetics: insights into ligand conformation and ligand-receptor interactions / L. Belvisi, M. Civera, C. Gennari, I. Guzzetti, U. Piarulli, D. Potenza. ((Intervento presentato al 3. convegno Computationally Driven Drug Discovery tenutosi a Verona nel 2014.
Targeting protein-protein interactions in cancer with peptidomimetics: insights into ligand conformation and ligand-receptor interactions
L. BelvisiPrimo
;M. CiveraSecondo
;C. Gennari;I. Guzzetti;D. PotenzaUltimo
2014
Abstract
The importance and specificity of protein associations in cellular events and in the etiology of many pathologic processes make protein-protein interactions (PPI) attractive targets for therapeutic intervention. In cancer, some specific cell surface receptors - e.g. the aVb3, aVb5 and a5b1 integrins and several growth factor receptors – play key roles in tumor angiogenesis, progression and metastasis. The control of tumor cells proliferation is regulated by the activity of these receptors, through the formation of specific PP complexes. Hence, peptidomimetics mimicking the hot spots and the structural features of these protein interfaces represent a promising strategy for obtaining innovative drugs with an optimal pharmacological profile. Our research is aimed at developing an interdisciplinary approach to target integrin-mediated and other cancer-related PPI, based on the interplay between synthetic organic, computational, structural chemistry and biology. The communication will discuss the contribution of various computational techniques to the development of peptidomimetics capable of reproducing the RGD peptide epitope that mediates the interaction between extracellular matrix proteins and integrins in tumor angiogenesis. In particular, the combined use of molecular mechanics, molecular dynamics simulations and docking calculations with available structural information (x-ray, NMR) will be shown in defining the conformation of cyclic peptidomimetics containing rigid diketopiperazine scaffolds, and the ligand-integrin interactions at a molecular level. The different stereochemistry and the different substitution of the scaffold, as well as the RGD or RGD-like recognition sequence, strongly influence the conformations adopted in the free-state and the binding mode of these ligands in the active site of aVb3 and a5b1 integrins. The results will be compared to the results of competitive receptor binding assays, of cell adhesion experiments and of NMR interaction studies of the peptidomimetic ligands with aVb3- and a5b1-integrin rich intact cancer cells.Pubblicazioni consigliate
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