The CLAS12 Spectrometer at Jefferson Laboratory

The CEBAF Large Acceptance Spectrometer for operation at 12 GeV beam energy (CLAS12) in Hall B at Jefferson Laboratory is used to study electro-induced nuclear and hadronic reactions. This spectrometer provides efficient detection of charged and neutral particles over a large fraction of the full solid angle. CLAS12 has been part of the energy-doubling project of Jefferson Lab's Continuous Electron Beam Accelerator Facility, funded by the United States Department of Energy. An international collaboration of 48 institutions contributed to the design and construction of detector hardware, developed the software packages for the simulation of complex event patterns, and commissioned the detector systems. CLAS12 is based on a dual-magnet system with a superconducting torus magnet that provides a largely azimuthal field distribution that covers the forward polar angle range up to 35∘, and a solenoid magnet and detector covering the polar angles from 35° to 125° with full azimuthal coverage. Trajectory reconstruction in the forward direction using drift chambers and in the central direction using a vertex tracker results in momentum resolutions of <1% and <3%, respectively. Cherenkov counters, time-of-flight scintillators, and electromagnetic calorimeters provide good particle identification. Fast triggering and high data-acquisition rates allow operation at a luminosity of 1035 cm−2s−1. These capabilities are being used in a broad program to study the structure and interactions of nucleons, nuclei, and mesons, using polarized and unpolarized electron beams and targets for beam energies up to 11 GeV. This paper gives a general description of the design, construction, and performance of CLAS12

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016

Exploration of a Binding Mode of Benzothiazol-2-yl Acetonitrile Pyrimidine Core Based Derivatives as Potent c-Jun N-Terminal Kinase-3 Inhibitors and 3D-QSAR Analyses

C-Jun N-terminal kinase (JNK) is a therapeutic target for inhibitors which may provide clinical benefit in the pathogenesis of rheumatoid arthritis (RA) as well as in various apoptosis-related disorders. The benzothiazol-2-yl acetonitrile derivatives, recently reported by Pascale et al. (J. Med. Chem. 2005, 48, 4596- 4607), are the first generation JNK inhibitors of this class. To understand inhibitory mechanisms and elucidate pharmacophoric properties of these derivatives molecular docking and 3D-QSAR studies were performed on a set of 44 compounds. Ligand Fit module of Cerius2 (4.9) was employed to locate the binding orientations of all the compounds within the JNK-3 ATP binding site. A good correlation (r2)0.810) between the calculated binding free energies (-PMF score) and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, robust and highly predictive 3D-QSAR models were developed with conventional r2 0.886 and 0.802, full cross-validation r2 0.980 and 0.788, and predictive r2 0.965 and 0.968 for MFA and MSA, respectively. The interaction mode was demonstrated taking into consideration inhibitor conformation, hydrogen bonding, and electrostatic interaction. The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders

Retraction notice to ‘‘A Computational Docking Study for Prediction of Binding mode of Diospyrin and Derivatives: Inhibitors of Human and Leishmanial DNA Topoisomerase-I’’

This retraction is due to use and publication of data by another group that was neither acknowledged nor credited and that was used against the wishes of the co-workers

Exploring the Structure of Opioid Receptors with Homology Modeling based on Single and Multiple Templates and Subsequent Docking: A Comparative Study

Opioid receptors are the principal targets for opioids, which have been used as analgesics for centuries. Opioid receptors belong to the rhodopsin family of G-protein coupled receptors (GPCRs). In the absence of crystal structures of opioid receptors, 3D homology models have been reported with bovine rhodopsin as a template, though the sequence homology is low. Recently, it has been reported that use of multiple templates results in a better model for a target having low sequence identity with a single template. With the objective of carrying out a comparative study on the structural quality of the 3D models based on single and multiple templates, the homology models for opioid receptors (mu, delta and kappa) were generated using bovine rhodopsin as single template and the recently deposited crystal structures of squid rhodopsin, turkey β-1 and human β-2 adrenoreceptors along with bovine rhodopsin as multiple templates. In this paper we report the results of comparison between the refined 3D models based on multiple sequence alignment (MSA) and models built with bovine rhodopsin as template, using validation programs PROCHECK, PROSA, Verify 3D, Molprobity and docking studies. The results indicate that homology models of mu and kappa with multiple templates are better than those built with only bovine rhodopsin as template, whereas, in many aspects, the homology model of delta opioid receptor with single template is better with respect to the model based on multiple templates. Three nonselective ligands were docked to both the models of mu, delta and kappa opioid receptors using GOLD 3.1. The results of docking complied well with the pharamacophore, reported for nonspecific opioid ligands. The comparison of docking results for models with multiple templates and those with single template have been discussed in detail. Three selective ligands for each receptor were also docked. As the crystallographic structures are not yet known, this comparison will help in choosing better homology models of opioid receptors for studying ligand receptor interactions to design new potent opioid antagonists

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads

<p>Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer’s disease therapeutics.</p

Deciphering the Binding Mode of Zolpidem to GABAA α1 Receptor – Insights from Molecular Dynamics Simulation

To investigate the binding mode of Zolpidem to GABAA and to delineate the conformational changes induced upon agonist binding, we carried out atomistic molecular dynamics simulation using the ligand binding domain of GABAA α1 receptor. Comparative molecular dynamics simulation of the apo and the holo form of GABAA receptor revealed that γ2/α1 interface housing the benzodiazepine binding site undergoes distinct conformational changes upon Zolpidem binding. We notice that C loop of the α1 subunit experiences an inward motion toward the vestibule and the F loop of γ2 sways away from the vestibule, an observation that rationalizes Zolpidem as an alpha1 selective agonist. Energy decomposition analysis carried out was able to highlight the important residues implicated in Zolpidem binding, which were largely in congruence with the experimental data. The simulation study disclosed herein provides a meaningful insight into Zolpidem-GABAAR interactions and helps to arrive at a binding mode hypothesis with implications for drug design