233 research outputs found
Accelerating drug target inhibitor discovery with a deep generative foundation model
Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information
A Search for Jet Handedness in Hadronic Decays
We have searched for signatures of polarization in hadronic jets from decays using the ``jet handedness'' method. The polar angle
asymmetry induced by the high SLC electron-beam polarization was used to
separate quark jets from antiquark jets, expected to be left- and
right-polarized, respectively. We find no evidence for jet handedness in our
global sample or in a sample of light quark jets and we set upper limits at the
95% C.L. of 0.063 and 0.099 respectively on the magnitude of the analyzing
power of the method proposed by Efremov {\it et al.}Comment: Revtex, 8 pages, 2 figure
Measurement of the Charged Multiplicities in b, c and Light Quark Events from Z0 Decays
Average charged multiplicities have been measured separately in , and
light quark () events from decays measured in the SLD experiment.
Impact parameters of charged tracks were used to select enriched samples of
and light quark events, and reconstructed charmed mesons were used to select
quark events. We measured the charged multiplicities:
,
, from
which we derived the differences between the total average charged
multiplicities of or quark events and light quark events: and . We compared
these measurements with those at lower center-of-mass energies and with
perturbative QCD predictions. These combined results are in agreement with the
QCD expectations and disfavor the hypothesis of flavor-independent
fragmentation.Comment: 19 pages LaTex, 4 EPS figures, to appear in Physics Letters
EUROCarbDB: An open-access platform for glycoinformatics
The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocar
Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
Summary:
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic “lipid-altered” tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug
EUROCarbDB: An open-access platform for glycoinformatics
The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb
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