Molecular dynamics directed CoMFA studies on carbocyclic neuraminidase inhibitors

Zanamivir is the known potent anti-influenza agent targeting the key enzyme neuraminidase that cleaves sialic acid from cell receptors allowing release of newly formed virions. Molecular dynamics simulation was carried out to determine the dynamic behavior of Zanamivir upon its binding to flexible loops of neuraminidase and to analyse its interactions in the bioactive state. Neuraminidase exhibits wide range of affinity with structurally similar compounds. CoMFA study was used to determine quantitative structure-activity relationship for 36 carbocyclic Neuraminidase inhibitors (NIs). The CoMFA model was also successfully built using cross-validated r²_cv = 0.580{{r}^{2}_{\rm cv} =0.580} and r²_pred=0.638{{r}^{2}_{\rm pred}=0.638} .     

Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H ₃₇Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3–93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r ²) of 0.98 and 0.95 with cross-validated r ²(q ²) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive ${r^{2} (r^{2}_{\rm pred})}$ is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.     

Parallel synthesis of novel antitumor agents: 1,2,3-triazoles bearing biologically active sulfonamide moiety and their 3D-QSAR

A 60-member 1,2,3-triazoles bearing biologically active sulfonamide moiety library was synthesized via azide–alkyne cycloaddition and examined for cytotoxic activity against human leukemia cell line HL-60. 25 of them were evaluated further in four additional cancer cell lines (HepG2, A549, PC3, SGC7901). Most of the 25 compounds showed moderate cytotoxic activities against the tested cell lines. Furthermore, the structure–activity relationships were discussed and a reliable 3D-QSAR model with good prediction (r_cv² = 0.64, r² = 0.958){\left(r_{\rm cv}^{2 } = 0.64, r^{2} = 0.958\right)} was generated on the basis of our synthesized 1,2,3-triazoles for their cytotoxic activities against the HL-60 cell line. The contour map of the CoMFA should aid in the design of new antitumor agents.     

An ab initio molecular dynamics study of ionic conductivity in hexagonal lithium lanthanum titanate oxide La0.5Li0.5TiO3

To date, the fastest lithium ion-conducting solid electrolytes known are the perovskite-type ABO₃ oxide, with A = Li, La and B = Ti, lithium lanthanum titanate (LLTO) Li_3x La_{( 2 \mathord}

Temperature dependence of the quenching of N<Subscript>2</Subscript> (C <Superscript>3</Superscript>Π<Subscript>u</Subscript>) by N<Subscript>2</Subscript> (X) and O<Subscript>2</Subscript> (X)

The temperature dependences of the quenching rate constants of the states N₂ (${\rm C} \ {^{3}{ \rm \Pi }_{u}}${\rm C} \ {^{3}{ \rm \Pi }_{u}} v^′=0,1) by N₂ (X) and of the state N₂ (${\rm C} \ {^{3}{ \rm \Pi }_{u}} \ v^{\prime}=0${\rm C} \ {^{3}{ \rm \Pi }_{u}} \ v^{\prime}=0) by O₂ (X) are studied. Time-resolved light emission from the gas was analyzed in the temperature range from 300 K to 210 K keeping the gas at constant density. In case of quenching by N₂ (X), the quenching rate constant for the vibrational level v^′= 0 increases by (13 ±3)% with gas cooling whereas the quenching rate constant for v^′= 1 decreases by (5.0 ±2.5)% in this temperature range. For quenching by O₂ (X), the quenching rate constant decreases by (3 ±2)% with gas cooling. The temperature variation of the N₂ (C ³Π_u v^′=0) emission intensity for pure nitrogen and dry air are calculated using the obtained quenching rate constants and is compared with the experimental data available in the literature.     

On the elliptic flow for nearly symmetric collisions and nuclear equation of state

We present the results of elliptic flow for the collision of nearly symmetric nuclei (₁₀Ne²⁰+ ₁₃Al²⁷_{10}{\rm Ne}^{20}+\,_{13}{\rm Al}^{27}, ₁₈Ar⁴⁰+ ₂₁Sc⁴⁵_{18}{\rm Ar}^{40}+\,_{21}{\rm Sc}^{45}, ₃₀Zn⁶⁴+ ₂₈Ni⁵⁸_{30}{\rm Zn}^{64}+\,_{28}{\rm Ni}^{58}, ₃₆Kr⁸⁶+ ₄₁Nb⁹³_{36}{\rm Kr}^{86}+\,_{41}{\rm Nb}^{93}) using the quantum molecular dynamics (QMD) model. General features of elliptic flow are investigated with the help of theoretical simulations. The simulations are performed at beam energies between 45 and 105 MeV /nucleon. A significant change can be seen from in-plane to out-of-plane elliptic flow of different fragments with incident energy. A comparison with experimental data is also made. Further, we show that elliptic flow for different fragments follows power-law dependence as given by the function C(A_tot)^tC{(A_{\rm tot})^\tau}.     

High energy radiation femtochemistry of water molecules: early electron-radical pairs processes

The damages triggered by ionizing radiation on chemical and biological targets depend on the survival probability of radicals produced in clusters of ionization-excitation events. In this paper, we report on femtolysis (FEMTOsecond radioLYSIS) of pure liquid water using an innovative laser produced high-energy, ultra-short electron bunches in the 2.5-15 MeV range and high energy radiation femtochemistry (HERF) measurements. The short-time monitoring of a primary reducing radical, hydrated electron e^-_aq^{-}_{aq}, has been performed in confined ionization spaces (nascent spurs). The calculated yield of hydrated electrons at early time, G(e^-_aq)_ETG({\rm e}^{-}_{aq})_{ET}, is estimated to be 6.5 ± 0.5 (number/100 eV) at t ~ 5 ps after the ultrafast energy deposition. This estimated value is high compare to (i) the available data of previous works that used scavenging techniques; (ii) the predictions of stochastic water radiolysis modelling for which the initial behaviour of hydrated electron is investigated in the framework of a classical diffusion regime of independent pairs. The HERF developments give new insights into the early ubiquitous radical escape probability in nascent aqueous spurs and emphasize the importance of short-lived solvent bridged electron-radical complexes [H₃O^+...{\rm H}_{3}{\rm O}^{+...}  e_aq^-{\rm e}_{aq}^{-} ..OH]_nH2O{\rm OH}]_{n{\rm H}_2{\rm O}} (non-independent pairs). A complete understanding of the G(e^-_aq)_ET{\rm e}^{-}_{aq})_{ET} value needs to account for quantum aspects of 1s-like trapped electron ground state and neoformed prototropic radicals that govern ultra-fast recombination processes within these non-independent pair configurations. Femtolysis data emphasize that within a time-dependent non-diffusion regime, spatio-temporal correlations between hydrated electron and nearest neighbours OH radical or hydrated proton (H₃O⁺{\rm H}_{3}{\rm O}^{+}) would assist ultrafast anisotropic 1D recombination within solvent bridged electron-radical complexes. The emerging HERF domain would provide guidance for understanding of ultrashort-lived sub-structure of tracks and stimulate future semi-quantum simulations on prethermal radical reactions.     

3D-QSAR,molecular dynamics simulations,and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors

Cancer is a second major disease after metabolic disorders where the number of cases of death is increasing gradually. Mammalian target of rapamycin (mTOR) is one of the most important targets for treatment of cancer, specifically for breast and lung cancer. In the present research work, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were performed on 50 compounds reported as mTOR inhibitors. Three different alignment methods were used, and among them, distill method was found to be the best method. In CoMFA, leave-one-out cross-validated coefficients \((q^{2})\), conventional coefficient \((r^{2})\), and predicted correlation coefficient \((r^{2}_{\mathrm{pred}})\) values were found to be 0.664, 0.992, and 0.652, respectively. CoMSIA study was performed in 25 different combinations of features, such as steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic. From this, a combination of steric, electrostatic, hydrophobic (SEH), and a combination of steric, electrostatic, hydrophobic, donor, and acceptor (SEHDA) were found as best combinations. In CoMSIA (SEHDA), \(q^{2}\), \(r^{2}\) and \(r^{2}_{\mathrm{pred}}\) were found to be 0.646, 0.977, and 0.682, respectively, while in the case of CoMSIA (SEH), the values were 0.739, 0.976, and 0.779, respectively. Contour maps were generated and validated by molecular dynamics simulation-assisted molecular docking study. Highest active compound 19, moderate active compound 15, and lowest active compound 42 were docked on mTOR protein to validate the results of our molecular docking study. The result of the molecular docking study of highest active compound 19 is in line with the outcomes generated by contour maps. Based on the features obtained through this study, six novel mTOR inhibitors were designed and docked. This study could be useful for designing novel molecules with increased anticancer activity.     

Multireference calculation of lifetime of A~2Π_u state in nitrogen-molecule cation

This paper utilizes multireference configuration interaction theory to calculate the lifetime of A2Πu state for nitrogen molecular ion N+2.It obtains the transition moment function for A2Πu→X2Σ+ g,Franck-Condon factors between vibrational levels of the two states.The calculated lifetimes are 16.81,14.62,13.10,12.18,11.40,and 11.64 μs forv'= 0,1,2,3,4,5 vibrational levels of A2Πu state,respectively,which are in excellent agreement with available experimental values.     

Lowest- Q2 measurement of the γp → Δ reaction: Probing the pionic contribution

To determine nonspherical angular-momentum amplitudes in hadrons at long ranges (low Q²), data were taken for the p(ˉe, e'p)π⁰ reaction in the Δ region at Q ² = 0.060 (GeV/c)² utilizing the magnetic spectrometers of the A1 Collaboration at MAMI. The results for the dominant transition magnetic dipole amplitude and the quadrupole to dipole ratios at W = 1232 MeV are , Re( )%, and Re( )%. These disagree with predictions of constituent quark models but are in reasonable agreement with lattice calculations with nonlinear (chiral) pion mass extrapolations, with chiral effective field theory, and with dynamical models with pion cloud effects. These results confirm the dominance, and general Q² variation, of the pionic contribution at large distances.     

Laser-based measurements of line strength, self- and pressure-broadening coefficients of the H35Cl R(3) absorption line in the first overtone region for pressures up to 1 MPa

A high-resolution spectrometer based on a vertical-cavity surface-emitting laser (VCSEL) was developed and used to determine the line strength S(T ₀)=12.53(11)×10⁻²¹ cm⁻¹/(molec cm⁻²) and the self-broadening coefficient g⁰_HCl=0.021787(61)\gamma^{0}_{\mathrm{HCl}}=0.021787(61)  cm⁻¹/atm of the R(3) absorption line in the first rovibrational overtone (2←0) band of H³⁵Cl. Furthermore, the first laser-based high-pressure study on the pressure broadening of HCl by He, N₂ and O₂(g⁰_N2=0.07292(5)\mathrm{O}_{2}(\gamma^{0}_{\mathrm{N}_{2}}=0.07292(5)  cm⁻¹/atm, g⁰_He=0.02113(1)\gamma^{0}_{\mathrm{He}}=0.02113(1)  cm⁻¹/atm, g⁰_O2=0.03978(6)\gamma^{0}_{\mathrm{O}_{2}}=0.03978(6)  cm⁻¹/atm) is presented covering pressures of up to 1 MPa. The results are compared to previously available low-pressure data.     

Torelli Theorem for the Deligne–Hitchin Moduli Space

Fix integers g ≥ 3 and r ≥ 2, with r ≥ 3 if g = 3. Given a compact connected Riemann surface X of genus g, let denote the corresponding Deligne–Hitchin moduli space. We prove that the complex analytic space determines (up to an isomorphism) the unordered pair , where is the Riemann surface defined by the opposite almost complex structure on X.     

Updated estimate of the muon magnetic momentusing revised results from <Emphasis Type="Italic">e</Emphasis><Superscript> + </Superscript><Emphasis Type="Italic">e</Emphasis><Superscript>-</Superscript>annihilation

A new evaluation of the hadronic vacuum polarization contribution to the muon magnetic moment is presented. We take into account the reanalysis of the low-energy e ⁺ e ^-annihilation cross section into hadrons by the CMD-2 Collaboration. The agreement between e ⁺ e ^-and spectral functions in the channel is found to be much improved. Nevertheless, significant discrepancies remain in the center-of-mass energy range between 0.85 and , so that we refrain from averaging the two data sets. The values found for the lowest-order hadronic vacuum polarization contributions are where the errors have been separated according to their sources: experimental, missing radiative corrections in e ⁺ e ^-data, and isospin breaking. The corresponding Standard Model predictions for the muon magnetic anomaly read where the errors account for the hadronic, light-by-light (LBL) scattering and electroweak contributions. The deviations from the measurement at BNL are found to be (1.9 ) and (0.7 ) for the e ⁺ e ^-- and -based estimates, respectively, where the second error is from the LBL contribution and the third one from the BNL measurement.Received: 7 September 2003, Published online: 30 October 2003     

A combined 3D-QSAR and molecular docking strategy to understand the binding mechanism of V600EB-RAF inhibitors

B-RAF is a member of the RAF protein kinase family involved in the regulation of cell growth, differentiation, and proliferation. It forms a part of conserved apoptosis signals through the RAS?CRAF?CMAPK pathway. ^V600EB-RAF protein has much potential for scientific research as therapeutic target due to its involvement in human melanoma cancer. In this work, a molecular modeling study was carried out for the first time with 3D-QSAR studies by following the docking protocol on three different data sets of ^V600EB-RAF inhibitors. Based on the co-crystallized compound (PDB ID: 1UWJ), a receptor-guided alignment method was utilized to derive reliable CoMFA and CoMSIA models. The selected CoMFA model gives the best statistical values (q ² =?0.753, r ² =?0.962). With the same alignment protocol, a statistically reliable CoMSIA model out of fourteen different combinations was also derived (q ² = 0.807, r ² = 0.961). The actual predictive powers of both models were rigorously validated with an external test set, which gave satisfactory predictive r ² values for CoMFA and CoMSIA models, 0.89 and 0.88, respectively. In addition, y-randomization test was also performed to validate our 3D-QSAR models. Contour maps from CoMFA and CoMSIA models supported statistical results, revealed important structural features responsible for biological activity within the active site and explained the correlation between biological activity and receptor?Cligand interactions. Based on the developed models few new structures were designed. The newly predicted structure (IIIa) showed higher inhibitory potency (pIC₅₀ 6.826) than that of the most active compound of the series.