188 research outputs found
In silico druggability assessment of the NUDIX hydrolase protein family as a workflow for target prioritization
Computational chemistry has now been widely accepted as a useful tool for shortening lead times in early drug discovery. When selecting new potential drug targets, it is important to assess the likelihood of finding suitable starting points for lead generation before pursuing costly high-throughput screening campaigns. By exploiting available high-resolution crystal structures, an in silico druggability assessment can facilitate the decision of whether, and in cases where several protein family members exist, which of these to pursue experimentally. Many of the algorithms and software suites commonly applied for in silico druggability assessment are complex, technically challenging and not always user-friendly. Here we applied the intuitive open access servers of DoGSite, FTMap and CryptoSite to comprehensively predict ligand binding pockets, druggability scores and conformationally active regions of the NUDIX protein family. In parallel we analyzed potential ligand binding sites, their druggability and pocket parameter using Schrödinger's SiteMap. Then an in silico docking cascade of a subset of the ZINC FragNow library using the Glide docking program was performed to assess identified pockets for large-scale small-molecule binding. Subsequently, this initial dual ranking of druggable sites within the NUDIX protein family was benchmarked against experimental hit rates obtained both in-house and by others from traditional biochemical and fragment screening campaigns. The observed correlation suggests that the presented user-friendly workflow of a dual parallel in silico druggability assessment is applicable as a standalone method for decision on target prioritization and exclusion in future screening campaigns
Correlated ab-initio calculations for ground-state properties of II-VI semiconductors
Correlated ab-initio ground-state calculations, using relativistic
energy-consistent pseudopotentials, are performed for six II-VI semiconductors.
Valence () correlations are evaluated using the coupled cluster approach
with single and double excitations. An incremental scheme is applied based on
correlation contributions of localized bond orbitals and of pairs and triples
of such bonds. In view of the high polarity of the bonds in II-VI compounds, we
examine both, ionic and covalent embedding schemes for the calculation of
individual bond increments. Also, a partitioning of the correlation energy
according to local ionic increments is tested. Core-valence ()
correlation effects are taken into account via a core-polarization potential.
Combining the results at the correlated level with corresponding Hartree-Fock
data we recover about 94% of the experimental cohesive energies; lattice
constants are accurate to \sim 1%; bulk moduli are on average 10% too large
compared with experiment.Comment: 10 pages, twocolumn, RevTex, 3 figures, accepted Phys. Rev.
Recent advances in electronic structure theory and their influence on the accuracy of ab initio potential energy surfaces
Recent advances in electronic structure theory and the availability of high speed vector processors have substantially increased the accuracy of ab initio potential energy surfaces. The recently developed atomic natural orbital approach for basis set contraction has reduced both the basis set incompleteness and superposition errors in molecular calculations. Furthermore, full CI calculations can often be used to calibrate a CASSCF/MRCI approach that quantitatively accounts for the valence correlation energy. These computational advances also provide a vehicle for systematically improving the calculations and for estimating the residual error in the calculations. Calculations on selected diatomic and triatomic systems will be used to illustrate the accuracy that currently can be achieved for molecular systems. In particular, the F+H2 yields HF+H potential energy hypersurface is used to illustrate the impact of these computational advances on the calculation of potential energy surfaces
Resonant inelastic soft-x-ray scattering spectra at the N1s and C1s edges of poly(pyridine-2,5-diyl)
Resonant inelastic scattering measurements of poly(pyridine-2,5-diyl) have
been performed at the N1s and C1s edges using synchrotron radiation. For
comparison, molecular orbital calculations of the spectra have been carried out
with the repeat unit as a model molecule of the polymer chain. The resonant
emission spectra show depletion of the p electron bands which is consistent
with symmetry selection and momentum conservation rules. The depletion is most
obvious in the resonant inelastic scattering spectra of carbon while the
nitrogen spectra are dominated by lone pair n orbital emission of s symmetry
and are less excitation energy dependent. By comparing the measurements to
calculations an isomeric dependence of the resonant spectra is found giving
preference to two of the four possible isomers in the polymer.Comment: 6 pages, 3 figures,
http://www.sciencedirect.com/science/article/pii/S036820489800354
A mathematical and computational review of Hartree-Fock SCF methods in Quantum Chemistry
We present here a review of the fundamental topics of Hartree-Fock theory in
Quantum Chemistry. From the molecular Hamiltonian, using and discussing the
Born-Oppenheimer approximation, we arrive to the Hartree and Hartree-Fock
equations for the electronic problem. Special emphasis is placed in the most
relevant mathematical aspects of the theoretical derivation of the final
equations, as well as in the results regarding the existence and uniqueness of
their solutions. All Hartree-Fock versions with different spin restrictions are
systematically extracted from the general case, thus providing a unifying
framework. Then, the discretization of the one-electron orbitals space is
reviewed and the Roothaan-Hall formalism introduced. This leads to a exposition
of the basic underlying concepts related to the construction and selection of
Gaussian basis sets, focusing in algorithmic efficiency issues. Finally, we
close the review with a section in which the most relevant modern developments
(specially those related to the design of linear-scaling methods) are commented
and linked to the issues discussed. The whole work is intentionally
introductory and rather self-contained, so that it may be useful for non
experts that aim to use quantum chemical methods in interdisciplinary
applications. Moreover, much material that is found scattered in the literature
has been put together here to facilitate comprehension and to serve as a handy
reference.Comment: 64 pages, 3 figures, tMPH2e.cls style file, doublesp, mathbbol and
subeqn package
The electronic structure of poly(pyridine-2,5-diyl) investigated by soft x-ray absorption and emission spectroscopies
The electronic structure of the poly-pyridine conjugated polymer has been
investigated by resonant and nonresonant inelastic X-ray scattering and X-ray
absorption spectroscopies using synchrotron radiation. The measurements were
made for both the carbon and nitrogen contents of the polymer. The analysis of
the spectra has been carried out in comparison with molecular orbital
calculations taking the repeat-unit cell as a model molecule of the polymer
chain. The simulations indicate no significant differences in the absorption
and in the non-resonant X-ray scattering spectra for the different isomeric
geometries, while some isomeric dependence of the resonant spectra is
predicted. The resonant emission spectra show depletion of the {\pi} electron
bands in line with symmetry selection and momentum conservation rules. The
effect is most vizual for the carbon spectra; the nitrogen spectra are
dominated by lone pair n orbital emission of {\sigma} symmetry and are less
frequency dependent.Comment: 11 pages, 7 figures, 1 table,
http://www.sciencedirect.com/science/article/pii/S030101049800262
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