In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists.

Ghrelin is a peptide hormone involved in multiple functions, including growth hormone release stimulation, food intake regulation, and metabolic and cytoprotective effect. A novel family of peptides with internal cycles was designed as ghrelin analogs and the biological activity of two of them (A228 and A233) was experimentally studied in-depth. In this work, an in silico strategy was developed for describing and assessing the binding modes of A228 and A233 to GHS-R1a (ghrelin receptor) comparing it with ghrelin and GHRP-6 peptides. Several reported structures of different G protein coupled receptors were used as templates, to obtain a good quality model of GHS-R1a. The best model was selected by preliminary molecular docking with ghrelin and GHRP-6. Docking was used to estimate peptide orientations in the binding site of the best model, observing a superposition of its N-terminal and its first aromatic residue. To test the complex stability in time, the C-terminal fragments of each peptide were added and the complexes were inserted a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, performing a molecular dynamic simulation for 100 ns using the CHARMM36 force field. Despite of the structural differences, the studied peptides share a common binding mode; the N-terminal interacts with E124 and the aromatic residue close to it, with the aromatic cluster (F279, F309, and F312). A preliminary pharmacophore model, consisting in a positive charged amine and an aromatic ring at an approximate distance of 0.79 nm, can be proposed. The results here described could represent a step forward in the efficient search of new ghrelin analogs.

Fisiopatología de la enfermedad renal poliquística / Physiopathology of the polycystic renal disease

La enfermedad renal poliquística es una de las condiciones genéticas con peligro para la vida más frecuentes en las poblaciones humanas. Se produce por mutaciones en los genes de algunas proteínas de las estructuras ciliares que modifica varias de las vías claves para la señalización celular, e induce un fenotipo hiperproliferativo que genera la aparición de neoplasmas benignos, localizados principalmente en el riñón, donde provocan la formación de quistes y la destrucción progresiva del tejido activo, hasta llegar a la enfermedad renal crónica. En los últimos años se ha acumulado una gran cantidad de información sobre la fisiopatología de la enfermedad y se ha hecho posible el surgimiento de estrategias nuevas para el tratamiento, que se encuentran en ensayos clínicos en todo el mundo(AU)

Polycystic Kidney Disease is one the most frequent life threatening genetic disease in the human population. The etiology is the defect on the genes coding for several proteins on the cell cilia, modifying key signaling pathways to induce a hyperproliferative phenotype and the development of benign neoplasms localized mainly on the kidneys, provoking the progressive destruction of the active tissue and the end stage renal disease. In the recent years many information has been gathered on the pathophysiology of the disease, making possible the devise of new treatment strategies in clinical trials through the world(AU)