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Keywords: drug development 

Neutron crystallography to inform drug design targeting SARS-CoV-2 main protease

Talk from one of the ILL colloqia. See colloquia list at the bottom for other talks. COVID-19, caused by SARS-CoV-2, remains a global health threat after two years of the pandemic even with available vaccines and therapeutic options. The viral main protease (Mpro) is indispensable for the...

Keywords: COVID research, neutron, drug development, neutron crystallography

Resource type: video, slides

Neutron crystallography to inform drug design targeting SARS-CoV-2 main protease https://pan-training.eu/materials/neutron-crystallography-to-inform-drug-design-targeting-sars-cov-2-main-protease Talk from one of the ILL colloqia. See colloquia list at the bottom for other talks. COVID-19, caused by SARS-CoV-2, remains a global health threat after two years of the pandemic even with available vaccines and therapeutic options. The viral main protease (Mpro) is indispensable for the virus replication and thus is an important target for small-molecule antivirals. Computer-assisted and structure-based drug design strategies rely on atomic scale understanding of the target biomacromolecule traditionally derived from X-ray crystallographic data collected at cryogenic temperatures. Conventional protein X-ray crystallography is limited by possible cryo-artifacts and its inability to locate the functional hydrogen atoms crucial for understanding chemistry occurring in enzyme active sites. Neutrons are ideal probes to observe the protonation states of ionizable amino acids at near-physiological temperature, directly determining their electric charges – crucial information for drug design. Our room-temperature X-ray crystal structures of Mpro brought rapid insights into the reactivity of the catalytic cysteine, malleability of the active site, and binding modes with clinical protease inhibitors. The neutron crystal structures of ligand-free and inhibitor-bound Mpro were determined allowing the direct observation of protonation states of all residues in a coronavirus protein for the first time [1,2]. At rest, the catalytic Cys-His dyad exists in the reactive zwitterionic state (Fig. 1), with both Cys145 and His41 charged, instead of the anticipated neutral state. Covalent inhibitor binding results in modulation of the protonation states. This information was used to design nanomolar hybrid reversible covalent inhibitors with robust antiviral properties. High-throughput virtual screening, utilizing ORNL’s supercomputing capabilities, in conjunction with in vitro assays identified a lead noncovalent compound with sub-micromolar affinity. The neutron structure of Mpro in complex with the noncovalent inhibitor was used in a structure-activity relationship (SAR) study guided by virtual reality structure analysis to novel Mpro inhibitors with imporved affinity to the enzyme [3]. Our research is providing real-time data for atomistic design and discovery of Mpro inhibitors to combat the COVID-19 pandemic and prepare for future threats from pathogenic coronaviruses. [1] D.W. Kneller et al. Unusual zwitterionic catalytic site of SARS-CoV-2 main protease revealed by neutron crystallography. J. Biol. Chem.295, 17365-17373 (2020). [2] D.W. Kneller et al. Direct observation of protonation state modulation in SARS-CoV-2 main protease upon inhibitor binding with neutron crystallography. J. Med. Chem.64, 4991-5000 (2021). [3] D.W. Kneller et al. Structural, electronic and electrostatic determinants for inhibitor binding to subsites S1 and S2 in SARS-CoV-2 main protease. J. Med. Chem.64, 17366-17383 (2021). The authors acknowledge support by the National Virtual Biotechnology Laboratory, US Department of Energy. COVID research, neutron, drug development, neutron crystallography
DOI, FAIR and MX COVID-19 use case

Frank von Delft presents: DOI, FAIR and MX COVID-19 use case at the 2nd PaNOSC and ExPaNDS PaN EOSC Symposium (October 2021).

Keywords: COVID research, FAIR, fragalysis, drug development, XChem, PDB, zenodo, wp5-ExPaNDS

Resource type: video, slides

DOI, FAIR and MX COVID-19 use case https://pan-training.eu/materials/doi-fair-and-mx-covid-19-use-case Frank von Delft presents: DOI, FAIR and MX COVID-19 use case at the 2nd PaNOSC and ExPaNDS PaN EOSC Symposium (October 2021). COVID research, FAIR, fragalysis, drug development, XChem, PDB, zenodo, wp5-ExPaNDS
Introduction to Liquid-State Nuclear Magnetic Resonance (NMR)

Introduction to Liquid-State Nuclear Magnetic Resonance (NMR) at the CERIC Slovenian partner facility, the Slovenian NMR Centre at the National Institute of Chemistry in Ljubljana To get more insights on NMR spectroscopy, watch also the video on Solid-state NMR at: https://youtu.be/RVMAKM6RnRM

Keywords: Liquid-state NMR, NMR, Nuclear Magnetic Resonance, life sciences, COVID research, nucleic acids research, biochemistry, drug development

Resource type: video

Introduction to Liquid-State Nuclear Magnetic Resonance (NMR) https://pan-training.eu/materials/introduction-to-liquid-state-nuclear-magnetic-resonance-nmr Introduction to Liquid-State Nuclear Magnetic Resonance (NMR) at the CERIC Slovenian partner facility, the Slovenian NMR Centre at the National Institute of Chemistry in Ljubljana To get more insights on NMR spectroscopy, watch also the video on Solid-state NMR at: https://youtu.be/RVMAKM6RnRM Liquid-state NMR, NMR, Nuclear Magnetic Resonance, life sciences, COVID research, nucleic acids research, biochemistry, drug development scientists researchers PhD students biochemists chemists