2,300 research outputs found
Recent advances in in silico target fishing
In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery. It is especially worth underlining the increasing implementation of machine learning in this field, both as a main target fishing approach and as a further development of already applied strategies. This review reports on the main in silico target fishing strategies, belonging to both ligand-based and receptor-based approaches, developed and applied in the last years, with a particular attention to the different web tools freely accessible by the scientific community for performing target fishing studies
Predicting Isoform-Selective Carbonic Anhydrase Inhibitors via Machine Learning and Rationalizing Structural Features Important for Selectivity
Carbonic anhydrases (CAs) catalyze the physiological hydration of carbon dioxide and are among the most intensely studied pharmaceutical target enzymes. A hallmark of CA inhibition is the complexation of the catalytic zinc cation in the active site. Human (h) CA isoforms belonging to different families are implicated in a wide range of diseases and of very high interest for therapeutic intervention. Given the conserved catalytic mechanisms and high similarity of many hCA isoforms, a major challenge for CA-based therapy is achieving inhibitor selectivity for hCA isoforms that are associated with specific pathologies over other widely distributed isoforms such as hCA I or hCA II that are of critical relevance for the integrity of many physiological processes. To address this challenge, we have attempted to predict compounds that are selective for isoform hCA IX, which is a tumor-associated protein and implicated in metastasis, over hCA II on the basis of a carefully curated data set of selective and nonselective inhibitors. Machine learning achieved surprisingly high accuracy in predicting hCA IX-selective inhibitors. The results were further investigated, and compound features determining successful predictions were identified. These features were then studied on the basis of X-ray structures of hCA isoform-inhibitor complexes and found to include substructures that explain compound selectivity. Our findings lend credence to selectivity predictions and indicate that the machine learning models derived herein have considerable potential to aid in the identification of new hCA IX-selective compounds
Phonon Dynamics and Multipolar Isomorphic Transition in beta-pyrochlore KOs2O6
We investigate with a microscopic model anharmonic K-cation oscillation
observed by neutron experiments in beta-pyrochlore superconductor KOs2O6, which
also shows a mysterious first-order structural transition at Tp=7.5 K. We have
identified a set of microscopic model parameters that successfully reproduce
the observed temperature dependence and the superconducting transition
temperature. Considering changes in the parameters at Tp, we can explain
puzzling experimental results about electron-phonon coupling and neutron data.
Our analysis demonstrates that the first-order transition is multipolar
transition driven by the octupolar component of K-cation oscillations. The
octupole moment does not change the symmetry and is characteristic to
noncentrosymmetric K-cation potential.Comment: 5 pages, 4 figures, submitted to J. Phys. Soc. Jp
Superconductivity and Rattling under High Pressure in the beta-Pyrochlore Oxide RbOs2O6
Rattling-induced superconductivity in the beta-pyrochlore oxide RbOs2O6 is
investigated under high pressures up to 6 GPa. Resistivity measurements in a
high-quality single crystal show that the superconducting transition
temperature Tc increases gradually from 6.3 K at ambient pressure to 8.8 K at
3.5 GPa, surprisingly remains almost constant at 8.8 \pm 0.1 K in a wide
pressure range between 3.5 (Po) and 4.8 GPa, and suddenly drops to 6.3 K at Ps
= 4.9 GPa, followed by a gradual decrease with further pressure increase. Two
anomalies in the temperature dependence of the normal-state resistivity are
observed at Po Ps, revealing the presence of two high-pressure
phases corresponding to the changes in Tc. The rattling of the Rb ion inside a
cage made of Os and O atoms may be slightly and seriously modified in these
high-pressure phases that probably have cages of reduced symmetry,
respectively, so that electron-rattler interactions that govern the
superconducting and transport properties of beta-RbOs2O6 are significantly
affected.Comment: arXiv admin note: text overlap with arXiv:1009.035
Observation of nu_tau appearance in the CNGS beam with the OPERA experiment
The OPERA experiment is searching for nu_mu -> nu_tau oscillations in
appearance mode i.e. via the direct detection of tau leptons in nu_tau charged
current interactions. The evidence of nu_mu -> nu_tau appearance has been
previously reported with three nu_tau candidate events using a sub-sample of
data from the 2008-2012 runs. We report here a fourth nu_tau candidate event,
with the tau decaying into a hadron, found after adding the 2012 run events
without any muon in the final state to the data sample. Given the number of
analysed events and the low background, nu_mu -> nu_tau oscillations are
established with a significance of 4.2sigma.Comment: Submitted to Progress of Theoretical and Experimental Physics (PTEP
Determination of the muon charge sign with the dipolar spectrometers of the OPERA experiment
The OPERA long-baseline neutrino-oscillation experiment has observed the
direct appearance of in the CNGS beam. Two large muon
magnetic spectrometers are used to identify muons produced in the
leptonic decay and in interactions by measuring their charge and
momentum. Besides the kinematic analysis of the decays, background
resulting from the decay of charmed particles produced in
interactions is reduced by efficiently identifying the muon track. A new method
for the charge sign determination has been applied, via a weighted angular
matching of the straight track-segments reconstructed in the different parts of
the dipole magnets. Results obtained for Monte Carlo and real data are
presented. Comparison with a method where no matching is used shows a
significant reduction of up to 40\% of the fraction of wrongly determined
charges.Comment: 10 pages. Improvements in the tex
Evidence for appearance in the CNGS neutrino beam with the OPERA experiment
The OPERA experiment is designed to search for oscillations in appearance mode i.e. through the direct observation
of the lepton in charged current interactions. The
experiment has taken data for five years, since 2008, with the CERN Neutrino to
Gran Sasso beam. Previously, two candidates with a decaying
into hadrons were observed in a sub-sample of data of the 2008-2011 runs. Here
we report the observation of a third candidate in the
decay channel coming from the analysis of a sub-sample of the
2012 run. Taking into account the estimated background, the absence of
oscillations is excluded at the 3.4
level.Comment: 9 pages, 5 figures, 1 table
Procedure for short-lived particle detection in the OPERA experiment and its application to charm decays
The OPERA experiment, designed to perform the first observation of oscillations in appearance mode through the detection of
the leptons produced in charged current interactions, has
collected data from 2008 to 2012. In the present paper, the procedure developed
to detect particle decays, occurring over distances of the order of 1 mm
from the neutrino interaction point, is described in detail. The results of its
application to the search for charmed hadrons are then presented as a
validation of the methods for appearance detection
Limits on muon-neutrino to tau-neutrino oscillations induced by a sterile neutrino state obtained by OPERA at the CNGS beam
The OPERA experiment, exposed to the CERN to Gran Sasso beam,
collected data from 2008 to 2012. Four oscillated Charged Current
interaction candidates have been detected in appearance mode, which are
consistent with oscillations at the atmospheric within the "standard" three-neutrino framework. In this paper, the OPERA
appearance results are used to derive limits on the mixing
parameters of a massive sterile neutrino.Comment: 11 pages, 4 figures; reference to Planck result updated in the
Introduction. Submitted to JHE
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