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In this work we present results from fully atomistic molecular dynamics simulations of aqueous solutions of poly(amido amine) dendrimers and poly(methacrylic) acid in the dilute regime and at low ionic strength and physiological pH conditions, in which the polymeric components are charged. We have studied stoichiometric (1:1) and non-stoichiometric (1:2) systems, comprised by dendrimers of two different generations and two different lengths of the linear polyelectrolyte. For all systems studied, a polymer-rich and a solvent-rich region is formed. The polymer-rich region consists of aggregated complexes between the polymeric components bearing similarities to percolated structures met in physical hydrogels. We examine morphological characteristics of the two components as well as the degree of ionic pairing between the different ionic moieties, providing information regarding the degree of physical adsorption of the linear chains on the dendrimer's surface and that of the respective counterions on the oppositely charged monomers. [ABSTRACT FROM AUTHOR]

Due to their relative easy synthesis and commercial availability, nanovectors based on dendrimers and dendrons are among the most utilized non-viral vectors for gene transfer. Concomitantly, recent advances in molecular simulations and computer architectures not only allow for accurate predictions of many structural, energetical, and eventual self-assembly features of these nanocarriers per se, but are able to yield fundamental information about the interactions of these nanovectors with their nucleic acid cargoes at a molecular level. In this work, we aim at reviewing some of our own efforts in the field of multiscale molecular modeling of these fascinating materials. This review is written by computational scientists for experimental scientists, with the specific purpose of illustrating the potentiality of these methodologies and the usefulness of multiscale molecular modeling as an innovative and complementary tool in their current research. [ABSTRACT FROM AUTHOR]

Elucidation of the genetic processes leading to neoplastic transformation has identified cancer-promoting molecular alterations that can be selectively targeted by rationally designed therapeutic agents. Protein kinases are druggable targets and have been studied intensively. New methodologies--including crystallography and three-dimensional modeling--have allowed the rational design of potent and selective kinase inhibitors that have already reached the clinical stage. However, despite the clinical success of kinase-targeted therapies, most patients that respond eventually relapse as a result of acquired resistance. Darwinian-type selection of secondary mutations seems to have a major role in this resistance. The emergence and/or expansion of tumor clones containing new mutations in the target kinase and that are drug-insensitive have been observed after chronic treatment. The resistance mechanisms to tyrosine kinase inhibitors, in particular secondary resistant mutations as a consequence of treatment, will be discussed in detail. In particular, this Review will focus on KIT and PDGFRA mutations, which are involved in the pathogenesis of gastrointestinal stromal tumors. Harnessing the selection of mutated variants developed to overcome these resistance mechanisms is an ongoing goal of current research and new strategies to overcome drug resistance is being envisaged. [ABSTRACT FROM AUTHOR]