scholarly journals A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1328 ◽  
Author(s):  
Eric S. Marsan ◽  
Craig A. Bayse
Keyword(s):  
Active Site ◽  
Polybrominated Diphenyl Ethers ◽  
Density Functional ◽  
Endocrine System ◽  
Halogen Bonding ◽  
Binding Energies ◽  
Active Site Residues ◽  
Iodothyronine Deiodinase ◽  
Donor Acceptor ◽  
Small Models

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe−) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C–X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C–X bond. The higher energy C–Br* and C–Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C–X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios.

scholarly journals Anion Recognition by Neutral and Cationic Iodotriazole Halogen Bonding Scaffolds

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 798
Author(s):  
Iñigo Iribarren ◽  
Goar Sánchez-Sanz ◽  
Cristina Trujillo
Keyword(s):  
Density Functional ◽  
Computational Study ◽  
Halogen Bond ◽  
Anion Recognition ◽  
Lone Pair ◽  
Halogen Bonding ◽  
Binding Energies ◽  
Bond Critical Point ◽  
Density Values ◽  
Intramolecular Hydrogen

A computational study of the iodide discrimination by different neutral and cationic iodotriazole halogen bonding hosts was carried out by means of Density Functional Theory. The importance of the size of the scaffold was highlighted and its impact observed in the binding energies and intermolecular X⋯I distances. Larger scaffolds were found to reduce the electronic repulsion and increase the overlap between the halide electron lone pair and the corresponding I-C antibonding orbital, increasing the halogen bonding interactions. Additionally, the planarity plays an important role within the interaction, and can be tuned using hydroxyl to perform intramolecular hydrogen bonds (IMHB) between the scaffold and the halogen atoms. Structures with IMHB exhibit stronger halogen bond interactions, as evidenced by the shorter intramolecular distances, larger electron density values at the bond critical point and more negative binding energies.

scholarly journals Dual-Function Enzyme Catalysis for Enantioselective Carbon–Nitrogen Bond Formation

2021 ◽  
Author(s):  
zhen liu ◽  
Carla Calvó-Tusell ◽  
Andrew Z. Zhou ◽  
kai chen ◽  
Marc Garcia-Borràs ◽  
...  
Keyword(s):  
Proton Transfer ◽  
Active Site ◽  
Density Functional ◽  
Dual Function ◽  
Cytochrome P450 Enzymes ◽  
Active Site Residues ◽  
Bond Forming ◽  
Enzymatic Transformation ◽  
Excellent Activity ◽  
Dynamics Simulations

<p>Whereas enzymatic asymmetric carbene N–H insertion is a powerful method for preparation of chiral amines in principle, it has suffered from limited enantioselectivity in practice. In this work, we demonstrate that engineered cytochrome P450 enzymes can catalyze this abiological C–N bond-forming reaction with excellent activity and selectivity (up to 32,100 TTN, >99% yield and 98% e.e.) to prepare a series of bioactive <i>α</i>-amino lactones, which have not been accessed previously using a carbene insertion strategy. The enzymes are dual-function catalysts, effecting both carbene transfer and enantioselective proton-transfer catalysis, in a single active site. To gain insight into the mechanism of the enzymatic transformation, especially in the asymmetric protonation step, we performed extensive molecular dynamics simulations and density functional theory (DFT) calculations. Computational studies uncover the important roles of active-site residues that enable high activity and selectivity through interacting with the carbene intermediate and the amine substrate, and directing water molecules for selective proton transfer.<br></p><p></p>

scholarly journals Dual-Function Enzyme Catalysis for Enantioselective Carbon–Nitrogen Bond Formation

2021 ◽  
Author(s):  
zhen liu ◽  
Carla Calvó-Tusell ◽  
Andrew Z. Zhou ◽  
kai chen ◽  
Marc Garcia-Borràs ◽  
...  
Keyword(s):  
Proton Transfer ◽  
Active Site ◽  
Density Functional ◽  
Dual Function ◽  
Cytochrome P450 Enzymes ◽  
Active Site Residues ◽  
Bond Forming ◽  
Enzymatic Transformation ◽  
Excellent Activity ◽  
Dynamics Simulations

<p>Whereas enzymatic asymmetric carbene N–H insertion is a powerful method for preparation of chiral amines in principle, it has suffered from limited enantioselectivity in practice. In this work, we demonstrate that engineered cytochrome P450 enzymes can catalyze this abiological C–N bond-forming reaction with excellent activity and selectivity (up to 32,100 TTN, >99% yield and 98% e.e.) to prepare a series of bioactive <i>α</i>-amino lactones, which have not been accessed previously using a carbene insertion strategy. The enzymes are dual-function catalysts, effecting both carbene transfer and enantioselective proton-transfer catalysis, in a single active site. To gain insight into the mechanism of the enzymatic transformation, especially in the asymmetric protonation step, we performed extensive molecular dynamics simulations and density functional theory (DFT) calculations. Computational studies uncover the important roles of active-site residues that enable high activity and selectivity through interacting with the carbene intermediate and the amine substrate, and directing water molecules for selective proton transfer.<br></p><p></p>

Designing of 5,10-Dihydroindolo [3,2-b] Indole (DINI) Based Donor Materials for Small Molecule Organic Solar Cells

2020 ◽  
pp. 2150005 ◽  
Author(s):  
Arooj Fatima ◽  
Afifa Farhat ◽  
Rabia Saleem ◽  
Rasheed Ahmad Khera ◽  
Saleem Iqbal ◽  
...  
Keyword(s):  
Organic Solar Cells ◽  
Density Functional ◽  
Transition Density ◽  
Open Circuit ◽  
Binding Energies ◽  
Strong Electron ◽  
Structural Modifications ◽  
Donor Acceptor ◽  
Reorganization Energies ◽  
Transition Density Matrix

In this paper, four small molecules B1, B2, B3 and B4 based on donor–acceptor–donor–acceptor–donor (D-A-D-A-D) combination were designed by making structural modifications in R. The designed molecules contain 5,10-dihydro-indolo [3,2-b] indole central donor core and different benzo-thiadiazole and fluorine substituted benzothiadiazole (FBT) acceptor units. These molecules have different subunits introduced on 5,10-dihydroindolo [3,2-b] indole central core like benzo [1,2,5] thiadiazole in (B1), 5-Fluoro-benzo [1,2,5] thiadiazole in (B2), 5-Methyl-benzo [1,2,5] thiadiazole in (B3), 2-Fluoro-2-methyl-2-H-benzotriazole unit in (B4), flanked with [2,2’,5’,2”] terthiophene as spacer (S) and triphenyl amine as a common end-capped donor in all the molecules (B1–B4). The optoelectronic properties of these molecules were studied by performing density functional theory (DFT) at CAM-B3LYP. Among all the designed structures, B2 showed maximum absorption (457[Formula: see text]nm) due to its strong electron withdrawing 5-Fluoro-benzo [1,2,5] thiadiazole acceptor unit. Other opto-electronic properties were analyzed through reorganization energies, density of electronic states and transition density matrix (TDM) to estimate the photovoltaic potential of these newly designed molecules. Low exciton binding energies and comparable values of open circuit voltage than R indicate the worth of these candidates to be used in future solar energy driven devices.

Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

2017 ◽  
Vol 14 (10) ◽  
pp. 1122-1137 ◽  
Author(s):  
Nivedita Singh ◽  
Parameswaran Saravanan ◽  
M.S. Thakur ◽  
Sanjukta Patra
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Signal Transduction Pathway ◽  
Docking Study ◽  
Primary Objective ◽  
Cgmp Level ◽  
Active Site Residues ◽  
Aromatic Fragment ◽  
Docking Approach ◽  
Free Energy Of Binding

Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP. When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed. Objective: The primary objective of the present study was to develop new xanthine based inhibitors targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold. Methods: Manual designing and parallel molecular docking approach were used for the development of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were used for final validation of most promising compounds. Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A active site pocket with a significant interaction pattern. This was further validated by screening different factors such as free energy of binding, inhibition constant and interacting active site residues in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was found that compound 39-42 formed selective interaction towards PDE9A over other members of the PDE superfamily. Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best sites for substitution for the generation of potent PDE9A inhibitors.

scholarly journals An enzymatic activation of formaldehyde for nucleotide methylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Charles Bou-Nader ◽  
Frederick W. Stull ◽  
Ludovic Pecqueur ◽  
Philippe Simon ◽  
Vincent Guérineau ◽  
...  
Keyword(s):  
Amino Acids ◽  
Thymidylate Synthase ◽  
Active Site ◽  
De Novo ◽  
Crystallographic Structure ◽  
De Novo Synthesis ◽  
Active Site Residues ◽  
Enzymatic Activation ◽  
Enzyme Cofactors ◽  
Unique Ability

AbstractFolate enzyme cofactors and their derivatives have the unique ability to provide a single carbon unit at different oxidation levels for the de novo synthesis of amino-acids, purines, or thymidylate, an essential DNA nucleotide. How these cofactors mediate methylene transfer is not fully settled yet, particularly with regard to how the methylene is transferred to the methylene acceptor. Here, we uncovered that the bacterial thymidylate synthase ThyX, which relies on both folate and flavin for activity, can also use a formaldehyde-shunt to directly synthesize thymidylate. Combining biochemical, spectroscopic and anaerobic crystallographic analyses, we showed that formaldehyde reacts with the reduced flavin coenzyme to form a carbinolamine intermediate used by ThyX for dUMP methylation. The crystallographic structure of this intermediate reveals how ThyX activates formaldehyde and uses it, with the assistance of active site residues, to methylate dUMP. Our results reveal that carbinolamine species promote methylene transfer and suggest that the use of a CH2O-shunt may be relevant in several other important folate-dependent reactions.

Sign in / Sign up

Export Citation Format

Share Document