Solid-state 17O NMR studies of organic and biological molecules

BackgroundLEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. They block HIV-1 integration by abrogating the interaction between LEDGF/p75 and IN as well as by allosterically inhibiting the catalytic activity of IN.ResultsHere we demonstrate that LEDGINs reduce the replication capacity of HIV particles produced in their presence. We systematically studied the molecular basis of this late effect of LEDGINs and demonstrate that HIV virions produced in their presence display a severe replication defect. Both the late effect and the previously described, early effect on integration contribute to LEDGIN antiviral activity as shown by time-of-addition, qPCR and infectivity assays. The late effect phenotype requires binding of LEDGINs to integrase without influencing proteolytic cleavage or production of viral particles. LEDGINs augment IN multimerization during virion assembly or in the released viral particles and severely hamper the infectivity of progeny virions. About 70% of the particles produced in LEDGIN-treated cells do not form a core or display aberrant empty cores with a mislocalized electron-dense ribonucleoprotein. The LEDGIN-treated virus displays defective reverse transcription and nuclear import steps in the target cells. The LEDGIN effect is possibly exerted at the level of the Pol precursor polyprotein.ConclusionOur results suggest that LEDGINs modulate IN multimerization in progeny virions and impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral particles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle.

LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions and reveal a role for LEDGF/p75 in late stage HIV-1 replication

The density functional method is used to obtain the molecular structure, electron density topography, and vibrational frequencies of the ion pair 1-ethyl-3-methylimidazolium acetate Different conformers are simulated on the basis of molecular interactions between the 1-ethyl-3-methylimidazolium cation and acetate anion The lowest energy conformers exhibit strong C−H···O interionic interactions compared with other conformers Characteristic vibrational frequencies of the ion pair and their shifts with respect to free ions are analyzed via the natural bond orbitals and difference electron density maps coupled with molecular electron density topology Theoretically scaled vibrational frequencies are also compared with the spontaneous Raman scattering and attenuated total reflection infrared absorption measurements

Molecular interactions in 1-ethyl-3-methylimidazolium acetate ion pair: a density functional study.

Density functional theory (DFT) is a widely used method for predicting equilibrium geometries of organometallic compounds involving transition metals, with a wide choice of functional and basis set combinations. A study of the role of basis set size in predicting the structural parameters can be insightful with respect to the effectiveness of using small basis sets to optimize larger molecular systems. For many organometallic systems, the metal–metal and metal–carbon distances are the most important structural features. In this study, we compare the equilibrium metal–ligand and metal–metal distances of six transition metal carbonyl compounds predicted by the Hood-Pitzer double-ζ polarization (DZP) basis set, against those predicted employing the standard correlation consistent cc-pVXZ (X = D,T,Q) basis sets, for 35 different DFT methods. The effects of systematically increasing the basis set size on the structural parameters are carefully investigated. The Mn–Mn bond distance in Mn2(CO)10 shows a greater ...

Investigating the Effects of Basis Set on Metal–Metal and Metal–Ligand Bond Distances in Stable Transition Metal Carbonyls: Performance of Correlation Consistent Basis Sets with 35 Density Functionals

DFT M06-2X investigation of alkaline hydrolysis of nitroaromatic compounds.

Presented work reports a comprehensive theoretical study on the inhibitory nature of N-arylnaphthylamines in Human Immunodeficiency Virus Integrase (HIV IN) - Lens Epithelium-Derived Growth Factor (LEDGF/p75) complexes. Factors influencing the inhibition efficiency in AlphaScreen% assay are evaluated and explained through the structure- and ligand-based studies; including molecular docking, molecular dynamics calculations, and quantitative structure-activity relationship (QSAR) approach. It has been shown that N-arylnaphthylamines possess a wide variety of binding poses. Three QSAR models have been developed using structural descriptors and descriptors derived from docking calculations. The activity of untested N-arylnaphthylamines have been predicted using the most successful model. Proposed here technique could become a useful tool for ligand selection, accelerating the development of a new generation of anti-HIV medications.Communicated by Ramaswamy H. Sarma.

N-arylnaphthylamines as inhibitors of human immunodeficiency virus integrase - lens epithelium-derived growth factor interactions: theoretical studies.

The reaction of 2-aryl-[1,2,4]triazolo[1,5-c]quinazolines with nucleophilic reagents (hydrazine hydrate, sodium hydroxide, sodium methoxide, hydrochloric acid) under acidic conditions leads to formation of compounds that tend to tautomerize. The products of the transformation are distinguished by the position (ortho-, meta-, para-) of the OCH3 group in the aryl moiety. To assign their structures we used the combined approach: experiment and theoretical modeling. The procedure included calculation of the relative stability for possible tautomers, simulation of UV/vis spectra for the most stable forms, and comparison of the resulting curves with the experimental spectral data taking into account the Boltzmann weighting. Through computations, we showed that the orientation of OCH3 substituent remarkably impacts on the tautomeric behavior of triazoles. In the case of ortho-OCH3 it is controlled by formation of the intramolecular hydrogen bond while for meta- and para- derivatives the degree of conjugation pla...

Correction to "Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole Derivatives: Combined Spectroscopic and Theoretical Study".

A quantum mechanical approach was proposed to determine the activation energy of surface diffusion for copper, nickel, zinc and iron atoms adsorbed on a copper substrate during electrocrystallization for various overvoltages of the substrate. The activation energy of surface diffusion was calculated from the crystal total energy. An increase in the activation energy of surface diffusion with increasing surface potential is associated with an increase in the binding energy between the ad-atom and the substrate.

Eugene O. Voronkov

Papers

N-arylnaphthylamines as inhibitors of human immunodeficiency virus integrase - lens epithelium-derived growth factor interactions: theoretical studies.

Correction to "Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole Derivatives: Combined Spectroscopic and Theoretical Study".

Quantum Mechanical Approach for Determining the Activation Energy of Surface Diffusion

Tautomeric behavior of 1,2,4-triazole derivatives: combined spectroscopic and theoretical study