Dual targeting of 3CLpro and PLpro of SARS-CoV-2: A novel structure-based design approach to treat COVID-19.

ABSTRACT

With the rapid growth of the COVID-19 (coronavirus disease 2019) pandemic across the globe, therapeutic attention must be directed to fight the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, developing new antiviral drugs and vaccines is time-consuming, so one of the best solutions to tackle this virus at present is to repurpose ready-to-use drugs. This paper proposes the repurposing of the Food and Drug Administration (FDA)-approved, purchasable, and naturally occurring drugs for preventive and therapeutic use. We propose to design a dual-inhibitor for the SARS-CoV-2 cysteine proteases-3 Chemotrypsin-like protease or main protease (3CLpro or Mpro) and Papain-like protease (PLpro) responsible for processing the translated polyprotein chain from the viral RNA yielding functional viral proteins. For virtual screening, an unbiased blind docking was performed from which the top nine dual-targeting inhibitors for 3CLpro and PLpro were selected. The nine repurposed drugs, block the catalytic dyad (His41 and Cys145) of 3CLpro as well as the catalytic triad (Cys111, His272, and Asp286) of PLpro. Repurposing known drugs will not only pave the way for rapid in-vitro and in-vivo studies to battle the SARS-CoV-2 but will also expedite the quest for a potent anti-coronaviral drug.