Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring

We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-b]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO2, -CF3, and -CH3) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds 1–18, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds 6 and 16 decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC50) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with FDI-6, in contrast to compound 1, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds 1–18 in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density

Combined dark matter searches towards dwarf spheroidal galaxies with Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS

Cosmological and astrophysical observations suggest that 85\% of the total matter of the Universe is made of Dark Matter (DM). However, its nature remains one of the most challenging and fundamental open questions of particle physics. Assuming particle DM, this exotic form of matter cannot consist of Standard Model (SM) particles. Many models have been developed to attempt unraveling the nature of DM such as Weakly Interacting Massive Particles (WIMPs), the most favored particle candidates. WIMP annihilations and decay could produce SM particles which in turn hadronize and decay to give SM secondaries such as high energy $\gamma$ rays. In the framework of indirect DM search, observations of promising targets are used to search for signatures of DM annihilation. Among these, the dwarf spheroidal galaxies (dSphs) are commonly favored owing to their expected high DM content and negligible astrophysical background. In this work, we present the very first combination of 20 dSph observations, performed by the Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS collaborations in order to maximize the sensitivity of DM searches and improve the current results. We use a joint maximum likelihood approach combining each experiment's individual analysis to derive more constraining upper limits on the WIMP DM self-annihilation cross-section as a function of DM particle mass. We present new DM constraints over the widest mass range ever reported, extending from 5 GeV to 100 TeV thanks to the combination of these five different $\gamma$-ray instruments

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data

Measurement of the dependence of the hadron production fraction ratio fs/fuf_\mathrm{s} / f_\mathrm{u} and fd/fuf_\mathrm{d} / f_ \mathrm{u} on B meson kinematic variables in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe dependence of the ratio between the B$_\mathrm{s}^0$ and B$^+$ hadron production fractions, $f_\mathrm{s} / f_\mathrm{u}$, on the transverse momentum ($p_\mathrm{T}$) and rapidity of the B mesons is studied using the decay channels B$_\mathrm{s}^0$$\to$ J$/\psi\,\phi$ and B$^+$$\to$ J$/\psi$ K$^+$. The analysis uses a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the CMS experiment in 2018 and corresponding to an integrated luminosity of 61.6 fb$^{-1}$. The $f_\mathrm{s} / f_\mathrm{u}$ ratio is observed to depend on the B $p_\mathrm{T}$ and to be consistent with becoming asymptotically constant at large $p_\mathrm{T}$. No rapidity dependence is observed. The ratio of the B$^0$ to B$^+$ hadron production fractions, $f_\mathrm{d} / f_\mathrm{u}$, measured using the B$^0$$\to$ J$/\psi$ K$^{*0}$ decay channel, is found to be consistent with unity and independent of $p_\mathrm{T}$ and rapidity, as expected from isospin invariance

Measurement of the double-differential inclusive jet cross section in proton-proton collisions at s\sqrt{s} = 5.02 TeV

International audienceThe inclusive jet cross section is measured as a function of jet transverse momentum $p_\mathrm{T}$ and rapidity $y$. The measurement is performed using proton-proton collision data at $\sqrt{s}$ = 5.02 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 27.4 pb$^{-1}$. The jets are reconstructed with the anti-$k_\mathrm{T}$ algorithm using a distance parameter of $R$ = 0.4, within the rapidity interval $\lvert y\rvert$$\lt$ 2, and across the kinematic range 0.06 $\lt$$p_\mathrm{T}$$\lt$ 1 TeV. The jet cross section is unfolded from detector to particle level using the determined jet response and resolution. The results are compared to predictions of perturbative quantum chromodynamics, calculated at both next-to-leading order and next-to-next-to-leading order. The predictions are corrected for nonperturbative effects, and presented for a variety of parton distribution functions and choices of the renormalization/factorization scales and the strong coupling $\alpha_\mathrm{S}$

Measurement of simplified template cross sections of the Higgs boson produced in association with W or Z bosons in the H →bb‾ \to \mathrm{b}\overline{\mathrm{b}} decay channel in proton-proton collisions at s= \sqrt{s}= 13 TeV

Differential cross sections are measured for the standard model Higgs boson produced in association with vector bosons (W, Z) and decaying to a pair of b quarks. Measurements are performed within the framework of the simplified template cross sections. The analysis relies on the leptonic decays of the W and Z bosons, resulting in final states with 0, 1, or 2 electrons or muons. The Higgs boson candidates are either reconstructed from pairs of resolved b-tagged jets, or from single large distance parameter jets containing the particles arising from two b quarks. Proton-proton collision data at $\sqrt{s}=$ 13 TeV, collected by the CMS experiment in 2016--2018 and corresponding to a total integrated luminosity of 138 fb$^{-1}$, are analyzed. The inclusive signal strength, defined as the product of the observed production cross section and branching fraction relative to the standard model expectation, combining all analysis categories, is found to be $\mu=$ 1.15 $^{+0.22}_{-0.20}$. This corresponds to an observed (expected) significance of 6.3 (5.6) standard deviations.Differential cross sections are measured for the standard model Higgs boson produced in association with vector bosons (W, Z) and decaying to a pair of b quarks. Measurements are performed within the framework of the simplified template cross sections. The analysis relies on the leptonic decays of the W and Z bosons, resulting in final states with 0, 1, or 2 electrons or muons. The Higgs boson candidates are either reconstructed from pairs of resolved b-tagged jets, or from single large distance parameter jets containing the particles arising from two b quarks. Proton-proton collision data at $\sqrt{s}$ = 13 TeV, collected by the CMS experiment in 2016-2018 and corresponding to a total integrated luminosity of 138 fb$^{-1}$, are analyzed. The inclusive signal strength, defined as the product of the observed production cross section and branching fraction relative to the standard model expectation, combining all analysis categories, is found to be $\mu$ = 1.15$^{+0.22}_{-0.20}$. This corresponds to an observed (expected) significance of 6.3 (5.6) standard deviations

Search for Higgs Boson and Observation of Z Boson through their Decay into a Charm Quark-Antiquark Pair in Boosted Topologies in Proton-Proton Collisions at s\sqrt{s} =13 TeV

A search for the standard model (SM) Higgs boson (H) produced with transverse momentum greater than 450 GeV and decaying to a charm quark-antiquark ($\mathrm{c\bar{c}}$) pair is presented. The search is performed using proton-proton collision data collected at $\sqrt{s}$ = 13 TeV by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb$^{-1}$. Boosted H $\to$$\mathrm{c\bar{c}}$ decay products are reconstructed as a single large-radius jet and identified using a deep neural network charm tagging technique. The method is validated by measuring the Z $\to$$\mathrm{c\bar{c}}$ decay process, which is observed in association with jets at high $p_\mathrm{T}$ for the first time with a signal strength of 1.00 $_{-0.14}^{+0.17}$ (syst) $\pm$ 0.08 (theo) $\pm$ 0.06 (stat), defined as the ratio of the observed process rate to the standard model expectation. The observed (expected) upper limit on $\sigma$(H) $\mathcal{B}$(H $\to$$\mathrm{c\bar{c}}$) is set at 47 (39) times the SM prediction at 95% confidence level

Search for top squark pair production in a final state with at least one hadronically decaying tau lepton in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for pair production of the supersymmetric partner of the top quark, the top squark, in proton-proton collisions at $\sqrt{s}$ = 13 TeV is presented in final states containing at least one hadronically decaying tau lepton and large missing transverse momentum. This final state is highly sensitive to scenarios of supersymmetry in which the decay of the top squark to tau leptons is enhanced. The search uses a data sample corresponding to an integrated luminosity of 138 fb$^{−1}$, which was recorded with the CMS detector during 2016–2018. No significant excess is observed with respect to the standard model predictions. Exclusion limits at 95% confidence level on the masses of the top squark and the lightest neutralino are presented under the assumptions of simplified models. The results probe top squark masses up to 1150 GeV for a nearly massless neutralino. This search covers a relatively less explored parameter space in the context of supersymmetry, and the exclusion limit is the most stringent to date for the model considered here.[graphic not available: see fulltext