{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:27:01Z","timestamp":1789003621747,"version":"build-2803163510"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    The design of effective target-specific drugs for COVID-19 treatment has become an intriguing challenge for modern science. The SARS-CoV-2 main protease, M\n                    <jats:sup>pro<\/jats:sup>\n                    , responsible for the processing of SARS-CoV-2 polyproteins and production of individual components of viral replication machinery, is an attractive candidate target for drug discovery. Specific M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors have turned out to be promising anticoronaviral agents. Thus, an effective platform for quantitative screening of M\n                    <jats:sup>pro<\/jats:sup>\n                    -targeting molecules is urgently needed. Here, we propose a pre\u2013steady-state kinetic analysis of the interaction of M\n                    <jats:sup>pro<\/jats:sup>\n                    with inhibitors as a basis for such a platform. We examined the kinetic mechanism of peptide substrate binding and cleavage by wild-type M\n                    <jats:sup>pro<\/jats:sup>\n                    and by its catalytically inactive mutant C145A. The enzyme induces conformational changes of the peptide during the reaction. The inhibition of M\n                    <jats:sup>pro<\/jats:sup>\n                    by boceprevir, telaprevir, GC-376, PF-00835231, or thimerosal was investigated. Detailed pre\u2013steady-state kinetics of the interaction of the wild-type enzyme with the most potent inhibitor, PF-00835231, revealed a two-step binding mechanism, followed by covalent complex formation. The C145A M\n                    <jats:sup>pro<\/jats:sup>\n                    mutant interacts with PF-00835231 approximately 100-fold less effectively. Nevertheless, the binding constant of PF-00835231 toward C145A M\n                    <jats:sup>pro<\/jats:sup>\n                    is still good enough to inhibit the enzyme. Therefore, our results suggest that even noncovalent inhibitor binding due to a fine conformational fit into the active site is sufficient for efficient inhibition. A structure-based virtual screening and a subsequent detailed assessment of inhibition efficacy allowed us to select two compounds as promising noncovalent inhibitor leads of SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fphar.2021.773198","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T10:03:41Z","timestamp":1638785021000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Pre-Steady-State Kinetics of the SARS-CoV-2 Main Protease as a Powerful Tool for Antiviral Drug Discovery"],"prefix":"10.3389","volume":"12","author":[{"given":"Maria Yu.","family":"Zakharova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra A.","family":"Kuznetsova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria I.","family":"Uvarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia D.","family":"Fomina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liubov I.","family":"Kozlovskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena N.","family":"Kaliberda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna N.","family":"Kurbatskaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan V.","family":"Smirnov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly A.","family":"Bulygin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera D.","family":"Knorre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga S.","family":"Fedorova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Varnek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry I.","family":"Osolodkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aydar A.","family":"Ishmukhametov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey M.","family":"Egorov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Gabibov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita A.","family":"Kuznetsov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1002\/JCC.23905","article-title":"DOCK 6: Impact of New Features and Current Docking Performance","volume":"36","author":"Allen","year":"2015","journal-title":"J. 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