2,652 research outputs found
When fragments link: A bibliometric perspective on the development of fragment-based drug discovery
Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions
Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength
Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Po
Spintronics: Fundamentals and applications
Spintronics, or spin electronics, involves the study of active control and
manipulation of spin degrees of freedom in solid-state systems. This article
reviews the current status of this subject, including both recent advances and
well-established results. The primary focus is on the basic physical principles
underlying the generation of carrier spin polarization, spin dynamics, and
spin-polarized transport in semiconductors and metals. Spin transport differs
from charge transport in that spin is a nonconserved quantity in solids due to
spin-orbit and hyperfine coupling. The authors discuss in detail spin
decoherence mechanisms in metals and semiconductors. Various theories of spin
injection and spin-polarized transport are applied to hybrid structures
relevant to spin-based devices and fundamental studies of materials properties.
Experimental work is reviewed with the emphasis on projected applications, in
which external electric and magnetic fields and illumination by light will be
used to control spin and charge dynamics to create new functionalities not
feasible or ineffective with conventional electronics.Comment: invited review, 36 figures, 900+ references; minor stylistic changes
from the published versio
Assembly of a π-π Stack of ligands in the binding site of an acetylcholine-binding protein
Acetylcholine-binding protein is a water-soluble homologue of the extracellular ligand-binding domain of cys-loop receptors. It is used as a structurally accessible prototype for studying ligand binding to these pharmaceutically important pentameric ion channels, in particular to nicotinic acetylcholine receptors, due to conserved binding site residues present at the interface between two subunits. Here we report that an aromatic conjugated small molecule binds acetylcholine-binding protein in an ordered π-π stack of three identical molecules per binding site, two parallel and one antiparallel. Acetylcholine-binding protein stabilizes the assembly of the stack by aromatic contacts. Thanks to the plasticity of its ligand-binding site, acetylcholine-binding protein can accommodate the formation of aromatic stacks of different size by simple loop repositioning and minimal adjustment of the interactions. This type of supramolecular binding provides a novel paradigm in drug design. © 2013 Macmillan Publishers Limited. All rights reserved
Differential (2+1) Jet Event Rates and Determination of alpha_s in Deep Inelastic Scattering at HERA
Events with a (2+1) jet topology in deep-inelastic scattering at HERA are
studied in the kinematic range 200 < Q^2< 10,000 GeV^2. The rate of (2+1) jet
events has been determined with the modified JADE jet algorithm as a function
of the jet resolution parameter and is compared with the predictions of Monte
Carlo models. In addition, the event rate is corrected for both hadronization
and detector effects and is compared with next-to-leading order QCD
calculations. A value of the strong coupling constant of alpha_s(M_Z^2)=
0.118+- 0.002 (stat.)^(+0.007)_(-0.008) (syst.)^(+0.007)_(-0.006) (theory) is
extracted. The systematic error includes uncertainties in the calorimeter
energy calibration, in the description of the data by current Monte Carlo
models, and in the knowledge of the parton densities. The theoretical error is
dominated by the renormalization scale ambiguity.Comment: 25 pages, 6 figures, 3 tables, submitted to Eur. Phys.
Multiplicity Structure of the Hadronic Final State in Diffractive Deep-Inelastic Scattering at HERA
The multiplicity structure of the hadronic system X produced in
deep-inelastic processes at HERA of the type ep -> eXY, where Y is a hadronic
system with mass M_Y< 1.6 GeV and where the squared momentum transfer at the pY
vertex, t, is limited to |t|<1 GeV^2, is studied as a function of the invariant
mass M_X of the system X. Results are presented on multiplicity distributions
and multiplicity moments, rapidity spectra and forward-backward correlations in
the centre-of-mass system of X. The data are compared to results in e+e-
annihilation, fixed-target lepton-nucleon collisions, hadro-produced
diffractive final states and to non-diffractive hadron-hadron collisions. The
comparison suggests a production mechanism of virtual photon dissociation which
involves a mixture of partonic states and a significant gluon content. The data
are well described by a model, based on a QCD-Regge analysis of the diffractive
structure function, which assumes a large hard gluonic component of the
colourless exchange at low Q^2. A model with soft colour interactions is also
successful.Comment: 22 pages, 4 figures, submitted to Eur. Phys. J., error in first
submission - omitted bibliograph
Multi-Jet Event Rates in Deep Inelastic Scattering and Determination of the Strong Coupling Constant
Jet event rates in deep inelastic ep scattering at HERA are investigated
applying the modified JADE jet algorithm. The analysis uses data taken with the
H1 detector in 1994 and 1995. The data are corrected for detector and
hadronization effects and then compared with perturbative QCD predictions using
next-to-leading order calculations. The strong coupling constant alpha_S(M_Z^2)
is determined evaluating the jet event rates. Values of alpha_S(Q^2) are
extracted in four different bins of the negative squared momentum
transfer~\qq in the range from 40 GeV2 to 4000 GeV2. A combined fit of the
renormalization group equation to these several alpha_S(Q^2) values results in
alpha_S(M_Z^2) = 0.117+-0.003(stat)+0.009-0.013(syst)+0.006(jet algorithm).Comment: 17 pages, 4 figures, 3 tables, this version to appear in Eur. Phys.
J.; it replaces first posted hep-ex/9807019 which had incorrect figure 4
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