Showing papers by "Ivanka Tsakovska published in 2015"

Computational Studies of Free Radical-Scavenging Properties of Phenolic Compounds.

Abstract: For more than half a century free radical-induced alterations at cellular and organ levels have been investigated as a probable underlying mechanism of a number of adverse health conditions. Consequently, significant research efforts have been spent for discovering more effective and potent antioxidants / free radical scavengers for treatment of these adverse conditions. Being by far the most used antioxidants among natural and synthetic compounds, mono- and polyphenols have been the focus of both experimental and computational research on mechanisms of free radical scavenging. Quantum chemical studies have provided a significant amount of data on mechanisms of reactions between phenolic compounds and free radicals outlining a number of properties with a key role for the radical scavenging activity and capacity of phenolics. The obtained quantum chemical parameters together with other molecular descriptors have been used in quantitative structure-activity relationship (QSAR) analyses for the design of new more effective phenolic antioxidants and for identification of the most useful natural antioxidant phenolics. This review aims at presenting the state of the art in quantum chemical and QSAR studies of phenolic antioxidants and at analysing the trends observed in the field in the last decade.

Structural and Dynamical Insight into PPARγ Antagonism: In Silico Study of the Ligand-Receptor Interactions of Non-Covalent Antagonists

Abstract: The structural and dynamical properties of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor have been broadly studied in its agonist state but little is known about the key features required for the receptor antagonistic activity. Here we report a series of molecular dynamics (MD) simulations in combination with free energy estimation of the recently discovered class of non-covalent PPARγ antagonists. Their binding modes and dynamical behavior are described in details. Two key interactions have been detected within the cavity between helices H3, H11 and the activation helix H12, as well as with H12. The strength of the ligand-amino acid residues interactions has been analyzed in relation to the specificity of the ligand dynamical and antagonistic features. According to our results, the PPARγ activation helix does not undergo dramatic conformational changes, as seen in other nuclear receptors, but rather perturbations that occur through a significant ligand-induced reshaping of the ligand-receptor and the receptor-coactivator binding pockets. The H12 residue Tyr473 and the charge clamp residue Glu471 play a central role for the receptor transformations. Our results also demonstrate that MD can be a helpful tool for the compound phenotype characterization (full agonists, partial agonists or antagonists) when insufficient experimental data are available.