RESUMEN
G-quadruplex nucleic acids are emerging as therapeutic targets for small molecules referred to as small-molecule G-quadruplex ligands. The porphyrin H(2)-TMPyP4 was early reported to be a suitable motif for G-quadruplex DNA recognition. It probably binds to G-quadruplex nucleic acid through π-π stacking with the external G-quartets. We explored chemical modifications of this porphyrin such as insertion of various metal ions in the centre of the aromatic core and addition of bulky substituents that may improve the specificity of the compound toward G-quadruplex DNA. Porphyrin metallation, affording a G4-ligand with two symmetric faces, allowed the conclusion that the presence of an axial water molecule perpendicular to the aromatic plane lowered but did not hamper π-π stacking interactions between the aromatic parts of the ligand on the one hand and the external G-quartet on the other. The charge introduced in the centre of the porphyrin had little influence on binding. Thus, the ionic channel in the centre of G-quadruplex nucleic acids was not found to provide clear additional molecular clues for G-quadruplex nucleic acids targeting by porphyrins tested in the present study. Furthermore, we confirmed the unique G-quadruplex selectivity of a porphyrin modified with four bulky substituents at the meso positions and showed that although the compound is not "drug-like" it was capable of entering cells in culture and mediated some of the typical cellular effects of small-molecule G-quadruplex ligands.
Asunto(s)
Inhibidores Enzimáticos/química , G-Cuádruplex , Porfirinas/química , Porfirinas/metabolismo , Sitios de Unión , Línea Celular , Proliferación Celular/efectos de los fármacos , Daño del ADN , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Transferencia Resonante de Energía de Fluorescencia , G-Cuádruplex/efectos de los fármacos , Humanos , Ligandos , Manganeso/química , Manganeso/metabolismo , Relación Estructura-Actividad , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismoRESUMEN
Our current understanding of ion permeation through the selectivity filter of the KcsA potassium channel is based on the concept of a multi-ion transport mechanism. The details of this concerted movement, however, are not well understood. In the present paper we report on molecular dynamics simulations which provides new insights. It is shown that ion translocation is based on the collective hopping of ions and water molecules which is mediated by the flexible charged carbonyl groups lining the backbone of the pore. In particular, there is strong evidence for pairwise translocations where one ion and one water molecule form a bound state. We suggest a physical explanation of the observed phenomena employing a simple lattice model. It is argued that the water molecules can act as rectifiers during the hopping of ion-water pairs.