Chemical Reaction of Soybean Flavonoids with DNA: A Computational Study Using the Implicit Solvent Model

Genistein, daidzein, glycitein and quercetin are flavonoids present in soybean and other vegetables in high amounts. These flavonoids can be metabolically converted to more active forms, which may react with guanine in the DNA to form complexes and can lead to DNA depurination. We assumed two ultimate carcinogen forms of each of these flavonoids, diol epoxide form and diketone form. Density functional theory (DFT) and Hartree-Fock (HF) methods were used to study the reaction thermodynamics between active forms of flavonoids and DNA guanine. Solvent reaction field method of Tomasi and co-workers and the Langevin dipoles method of Florian and Warshel were used to calculate the hydration free energies. Activation free energy for each reaction was estimated using the linear free energy relation. Our calculations show that diol epoxide forms of flavonoids are more reactive than the corresponding diketone forms and are hence more likely flavonoid ultimate carcinogens. Genistein, daidzein and glycitein show comparable reactivity while quercetin is less reactive toward DNA

The chemistry of neurodegeneration : kinetic data and their implications

We collected experimental kinetic rate constants for chemical processes responsible for the development and progress of neurodegeneration, focused on the enzymatic and non-enzymatic degradation of amine neurotransmitters and their reactive and neurotoxic metabolites. A gross scheme of neurodegeneration on the molecular level is based on two pathways. Firstly, reactive species oxidise heavy atom ions, which enhances the interaction with alpha-synuclein, thus promoting its folding to the beta form and giving rise to insoluble amyloid plaques. The latter prevents the function of vesicular transport leading to gradual neuronal death. In the second pathway, radical species, OH center dot in particular, react with the methylene groups of the apolar part of the lipid bilayer of either the cell or mitochondrial wall, resulting in membrane leakage followed by dyshomeostasis, loss of resting potential and neuron death. Unlike all other central neural system (CNS)-relevant biogenic amines, dopamine and noradrenaline are capable of a non-enzymatic auto-oxidative reaction, which produces hydrogen peroxide. This reaction is not limited to the mitochondrial membrane where scavenging enzymes, such as catalase, are located. On the other hand, dopamine and its metabolites, such as dopamine-o-quinone, dopaminechrome, 5,6-dihydroxyindole and indo-5,6-quinone, also interact directly with alpha-synuclein and reversibly inhibit plaque formation. We consider the role of the heavy metal ions, selected scavengers and scavenging enzymes, and discuss the relevance of certain foods and food supplements, including curcumin, garlic, N-acetyl cysteine, caffeine and red wine, as well as the long-term administration of non-steroid anti-inflammatory drugs and occasional tobacco smoking, that could all act toward preventing neurodegeneration. The current analysis can be employed in developing strategies for the prevention and treatment of neurodegeneration, and, hopefully, aid in the building of an overall kinetic molecular model of neurodegeneration itself

Determination of pKa values of Tyr residues in the active site of MAO A by performing computational simulations

Monoamineoxidase is mitochondrial flavoenzyme which plays essential role in a regulation of levels of biogenic monoamines in human body. MAO enzyme exists in two forms, MAO A and MAO B, as products of separate genes. Differences between two enzymes caused different therapy indications for MAO inhibitors as modern drugs. ...Structure-based drug design for diagnosis and treatment of neurological diseases, COST CM1103 Training School 9-13 September 2013 in Istanbul, Turke

Theoretical investigation of the differences in the ionization and hydrophobicity of the MAO A active site with and without serotonin

Monoamine oxidase (MAO) is a mitochondrial flavoenzyme which plays an essential role in the regulation of levels of biogenic monoamines in the human body and exists in two forms, MAO A and MAO B. Differences of two enzymes led to different therapy indications for MAO A and MAO B inhibitors [1]. ...Structure-based drug design for diagnosis and treatment of neurological diseases COST CM110

Computational scheme of histamine monocation interacting with five water molecules to calculate the free energy of hydration.

<p>The choice of the dielectric constant in the computations is indicated in round brackets.</p

Inhibition of specific binding of ³H- tiotidine in cultured astrocytes with histamine, 2- and 4-methylhistamine; 2-MeHi and 4-MeHi, respectively.

<p>Deuteration significantly (p < 0.0001) decreased the pIC₅₀ of 2-methylhistamine (8.38 ± 0.13 (control) to 6.85 ± 0.16 (D₂O)), whereas it significantly (p < 0.05) increased the pIC₅₀ of histamine (7.25 ± 0.11 (control) to 7.80 ± 0.16 (D₂O)) and marginally increased the pIC₅₀ value of 4-methylhistamine from 7.31 ± 0.28 (control) to 7.67 ± 0.13 (D₂O).</p

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

<div><p>In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to ³H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154002#pone.0154002.s001" target="_blank">S1 Table</a>) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. <i>Ab initio</i> quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains <i>in silico</i> discrimination between agonists and antagonists based on the receptor structure.</p></div