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Here, we show how the key factors governing cysteine reactivity in proteins derived from combined quantum mechanical\/continuum calculations led to a novel multi\u2010targeting strategy against SARS\u2010CoV\u20102, in contrast to developing potent drugs\/vaccines against a single viral target such as the spike protein. Specifically, they led to the discovery of reactive cysteines in evolutionary conserved Zn<jats:sup>2+<\/jats:sup>\u2010sites in several SARS\u2010CoV\u20102 proteins that are crucial for viral polypeptide proteolysis as well as viral RNA synthesis, proofreading, and modification. These conserved, reactive cysteines, both free and Zn<jats:sup>2+<\/jats:sup>\u2010bound, can be targeted using the same Zn\u2010ejector drug (disulfiram\/ebselen), which enables the use of broad\u2010spectrum anti\u2010virals that would otherwise be removed by the virus's proofreading mechanism. Our strategy of targeting multiple, conserved viral proteins that operate at different stages of the virus life cycle using a Zn\u2010ejector drug combined with other broad\u2010spectrum anti\u2010viral drug(s) could enhance the barrier to drug resistance and antiviral effects, as compared to each drug alone. Since these functionally important nonstructural proteins containing reactive cysteines are highly conserved among coronaviruses, our proposed strategy has the potential to tackle future coronaviruses.<\/jats:p><jats:p>This article is categorized under:<jats:list list-type=\"simple\">\n<jats:list-item><jats:p>Structure and Mechanism &gt; Reaction Mechanisms and Catalysis<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Structure and Mechanism &gt; Computational Biochemistry and Biophysics<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Electronic Structure Theory &gt; Density Functional Theory<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wcms.1607","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T11:14:26Z","timestamp":1646478866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["From quantum\u2010derived principles underlying cysteine 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