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10.1021/acs.jmedchem.1c00058 http://scihub22266oqcxt.onion/10.1021/acs.jmedchem.1c00058 33755450!8009097!33755450     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=33755450&cmd=llinks): Failed to open stream: HTTP request failed! 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Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography |pdf=|usr=}}{{33755450}} gab.com Text Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography JO: J Med Chem http://www.kidney.de/pget.php?&tw=1&pmid=33755450 #FOAvip The main protease (3CL M(pro)) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 M(pro). To aid rational drug design, we determined a neutron structure of M(pro) in complex with the alpha-ketoamide inhibitor telaprevir at near-physiological (22 degrees C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free M(pro), revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other alpha-ketoamide covalent inhibitors can lead to the same protonation state changes in the M(pro) active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 M(pro). Twit Text FOAVip Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography ????J Med Chem http://www.kidney.de/pget.php?&tw=1&pmid=33755450 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33755450 #FOAvip English Wikipedia <ref>{{Cite pmid|33755450}}</ref> Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography #MMPMID33755450 Kneller DW; Phillips G; Weiss KL; Zhang Q; Coates L; Kovalevsky A J Med Chem 2021[Apr]; 64 (8): 4991-5000 PMID33755450show ga The main protease (3CL M(pro)) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 M(pro). To aid rational drug design, we determined a neutron structure of M(pro) in complex with the alpha-ketoamide inhibitor telaprevir at near-physiological (22 degrees C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free M(pro), revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other alpha-ketoamide covalent inhibitors can lead to the same protonation state changes in the M(pro) active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 M(pro). |Binding Sites[MESH] |Coronavirus 3C Proteases/*antagonists & inhibitors/*chemistry/metabolism[MESH] |Crystallography, X-Ray[MESH] |Crystallography/methods[MESH] |Cysteine Proteinase Inhibitors/chemistry/metabolism[MESH] |Models, Molecular[MESH] |Neutrons[MESH] |Oligopeptides/*chemistry/metabolism[MESH] |Protein Conformation[MESH]Direct Observation of Protonation State Modulation in SARS-CoV-2 Main (epmc).pdf DeepDyve Pubget Overpricing