Fragment-to-Lead Medicinal Chemistry Publications in 2018

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.</p

High Temperature Electron Localization in dense He Gas

We report new accurate mesasurements of the mobility of excess electrons in high density Helium gas in extended ranges of temperature $[(26\leq T\leq 77) K ]$ and density $[ (0.05\leq N\leq 12.0) {atoms} \cdot {nm}^{-3}]$ to ascertain the effect of temperature on the formation and dynamics of localized electron states. The main result of the experiment is that the formation of localized states essentially depends on the relative balance of fluid dilation energy, repulsive electron-atom interaction energy, and thermal energy. As a consequence, the onset of localization depends on the medium disorder through gas temperature and density. It appears that the transition from delocalized to localized states shifts to larger densities as the temperature is increased. This behavior can be understood in terms of a simple model of electron self-trapping in a spherically symmetric square well.Comment: 23 pages, 13 figure

Energetics, forces, and quantized conductance in jellium modeled metallic nanowires

Energetics and quantized conductance in jellium modeled nanowires are investigated using the local density functional based shell correction method, extending our previous study of uniform in shape wires [C. Yannouleas and U. Landman, J. Phys. Chem. B 101, 5780 (1997)] to wires containing a variable shaped constricted region. The energetics of the wire (sodium) as a function of the length of the volume conserving, adiabatically shaped constriction leads to formation of self selecting magic wire configurations. The variations in the energy result in oscillations in the force required to elongate the wire and are directly correlated with the stepwise variations of the conductance of the nanowire in units of 2e^2/h. The oscillatory patterns in the energetics and forces, and the correlated stepwise variation in the conductance are shown, numerically and through a semiclassical analysis, to be dominated by the quantized spectrum of the transverse states at the narrowmost part of the constriction in the wire.Comment: Latex/Revtex, 11 pages with 5 Postscript figure

Importance of the Donor: Fullerene Intermolecular Arrangement for High-Efficiency Organic Photovoltaics

The performance of organic photovoltaic (OPV) material systems are hypothesized to depend strongly on the intermolecular arrangements at the donor:fullerene interfaces. A review of some of the most efficient polymers utilized in polymer:fullerene PV devices, combined with an analysis of reported polymer donor materials wherein the same conjugated backbone was used with varying alkyl substituents, supports this hypothesis. Specifically, the literature shows that higher-performing donor–acceptor type polymers generally have acceptor moieties that are sterically accessible for interactions with the fullerene derivative, whereas the corresponding donor moieties tend to have branched alkyl substituents that sterically hinder interactions with the fullerene. To further explore the idea that the most beneficial polymer:fullerene arrangement involves the fullerene docking with the acceptor moiety, a family of benzo[1,2-b:4,5-b′]dithiophene–thieno[3,4-c]pyrrole-4,6-dione polymers (PBDTTPD derivatives) was synthesized and tested in a variety of PV device types with vastly different aggregation states of the polymer. In agreement with our hypothesis, the PBDTTPD derivative with a more sterically accessible acceptor moiety and a more sterically hindered donor moiety shows the highest performance in bulk-heterojunction, bilayer, and low-polymer concentration PV devices where fullerene derivatives serve as the electron-accepting materials. Furthermore, external quantum efficiency measurements of the charge-transfer state and solid-state two-dimensional (2D) 13C{1H} heteronuclear correlation (HETCOR) NMR analyses support that a specific polymer:fullerene arrangement is present for the highest performing PBDTTPD derivative, in which the fullerene is in closer proximity to the acceptor moiety of the polymer. This work demonstrates that the polymer:fullerene arrangement and resulting intermolecular interactions may be key factors in determining the performance of OPV material systems

Approximate Bisimulations for Sodium Channel Dynamics

Abstract. This paper shows that, in the context of the Iyer et al. 67-variable cardiac myocycte model (IMW), it is possible to replace the detailed 13-state continuous-time MDP model of the sodium-channel dy-namics, with a much simpler Hodgkin-Huxley (HH)-like two-state sodium-channel model, while only incurring a bounded approximation error. The technical basis for this result is the construction of an approximate bisim-ulation between the HH and IMW channel models, both of which are input-controlled (voltage in this case) continuous-time Markov chains. The construction of the appropriate approximate bisimulation, as well as the overall result regarding the behavior of this modified IMW model, in-volves: (1) The identification of the voltage-dependent parameters of the m and h gates in the HH-type channel, based on the observations of the IMW channel. (2) Proving that the distance between observations of the two channels never exceeds a given error. (3) Exploring the sensitivity of the overall IMW model to the HH-type sodium-channel approximation. Our extensive simulation results experimentally validate our findings, for varying IMW-type input stimuli

ϒ production in p–Pb collisions at √sNN=8.16 TeV

ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.publishedVersio

(Anti-)deuteron production in pp collisions at 1as=13TeV

The study of (anti-)deuteron production in pp collisions has proven to be a powerful tool to investigate the formation mechanism of loosely bound states in high-energy hadronic collisions. In this paper the production of (anti-)deuterons is studied as a function of the charged particle multiplicity in inelastic pp collisions at s=13 TeV using the ALICE experiment. Thanks to the large number of accumulated minimum bias events, it has been possible to measure (anti-)deuteron production in pp collisions up to the same charged particle multiplicity (d Nch/ d \u3b7 3c 26) as measured in p\u2013Pb collisions at similar centre-of-mass energies. Within the uncertainties, the deuteron yield in pp collisions resembles the one in p\u2013Pb interactions, suggesting a common formation mechanism behind the production of light nuclei in hadronic interactions. In this context the measurements are compared with the expectations of coalescence and statistical hadronisation models (SHM)

Multiplicity dependence of inclusive J/psi production at midrapidity in pp collisions at root s=13 TeV

Measurements of the inclusive J/psi yield as a function of charged-particle pseudorapidity density dN(ch)/d eta in pp collisions at root s = 13 TeV with ALICE at the LHC are reported. The J/psi meson yield is measured at midrapidity (vertical bar y vertical bar <0.9) in the dielectron channel, for events selected based on the charged-particle multiplicity at midrapidity (vertical bar eta vertical bar <1) and at forward rapidity (-3.7 <eta <-1.7 and 2.8 <eta <5.1); both observables are normalized to their corresponding averages in minimum bias events. The increase of the normalized J/psi yield with normalized dN(ch)/d eta is significantly stronger than linear and dependent on the transverse momentum. The data are compared to theoretical predictions, which describe the observed trends well, albeit not always quantitatively. (C) 2020 European Organization for Nuclear Research. Published by Elsevier B.V.Peer reviewe

Centrality Dependence Of The Pseudorapidity Density Distribution For Charged Particles In Pb-pb Collisions At √snn=2.76tev

7264/Mai61062

Measurement of jet suppression in central Pb-Pb collisions at root s(NN)=2.76 TeV

The transverse momentum(p(T)) spectrum and nuclear modification factor (R-AA) of reconstructed jets in 0-10% and 10-30% central Pb-Pb collisions at root s(NN) = 2.76 TeV were measured. Jets were reconstructed using the anti-k(T) jet algorithm with a resolution parameter of R = 0.2 from charged and neutral particles, utilizing the ALICE tracking detectors and Electromagnetic Calorimeter (EMCal). The jet p(T) spectra are reported in the pseudorapidity interval of \eta(jet)\ 5 GeV/c to suppress jets constructed from the combinatorial background in Pb-Pb collisions. The leading charged particle requirement applied to jet spectra both in pp and Pb-Pb collisions had a negligible effect on the R-AA. The nuclear modification factor R-AA was found to be 0.28 +/- 0.04 in 0-10% and 0.35 +/- 0.04 in 10-30% collisions, independent of p(T), jet within the uncertainties of the measurement. The observed suppression is in fair agreement with expectations from two model calculations with different approaches to jet quenching. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V.Peer reviewe