key: cord-0828065-vnbxvhqu authors: Rajpoot, Sajjan; Alagumuthu, Manikandan; Baig, Mirza S. title: Dual Targeting of 3CL(pro) and PL(pro) of SARS-CoV-2: A Novel Structure-Based Design Approach to treat COVID-19 date: 2020-12-10 journal: Curr Res Struct Biol DOI: 10.1016/j.crstbi.2020.12.001 sha: cf839e2860d5c407e6907057a2a8a41f00bdcd9c doc_id: 828065 cord_uid: vnbxvhqu 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 vaccine development 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 as a dual-inhibitor for the SARS-CoV-2 cysteine proteases—3Chemotrypsin-like protease or main protease (3CL(pro) or M(pro)) and Papain-like protease (PL(pro))—that are responsible for processing the translated polyprotein chain from the viral RNA-yielding functional viral proteins. For virtual screening, an unbiased, blind docking was performed, which produced the top six dual-inhibition candidates for 3CL(pro) and PL(pro). The six repurposed drugs that have been proposed block the catalytic dyad His41 and Cys145 of 3CL(pro) as well as the catalytic triad Cys111, His272, and Asp286 along with oxyanion hole-stabilizing residue Trp106 of PL(pro) in the crystal structure. Repurposing such naturally occurring 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. In late December 2019, there was an outbreak of the new strain of the SARS-CoV-2, 31 spawning the coronavirus disease-2019 (COVID-19) pandemic. Since there are no specific 32 drugs or a vaccine to tackle the virus, the disease has taken hundreds of thousands of human 33 lives [1] [2] [3] . Presently, several strategies, including the use of broad-spectrum antiviral drugs, strongly suggest that such a treatment regimen of dual-target for COVID-19 may prove more 85 beneficial and may largely reduce the combinatorial drug application as well as multi-drug 86 dose burden in host system. Structural data retrieval and preparation-For molecular docking studies,the 89 experimentally solved low-resolutioncrystal structure of both the 3CL pro and PL pro available at 90 the PDB(Protein Data Bank) database was retrieved and prepared further for docking studies. The pdbfile format of the apo-enzyme structure of 3CL pro and PL pro (PDB ID 6M2Q and 92 6W9C,respectively) was downloaded from the PDB database (https://www.rcsb.org/). Beforedocking study, the water molecules were deleted and polar hydrogens were added to performed for each complex. The files were prepared for MD simulation in MDWeb server. The GROMOS 53a6 force field was applied and the whole system was solvated, equilibrated 119 and simulation was performed at constant temperature of 300 K.The stability of these protein- its load on the host. Considering the fact, the 3CL pro and PL pro were targeted to virtually 149 identify the potential drug specifically blocking its catalytic dyad and triad, respectively. Virtual screening of drugs was performed on the crystal structure of the targets. The 151 unmutated crystal structure 6M2Q for 3CL pro and 6W9C for PL pro from the PDB database 152 was selected (Fig. 1) we found a total of 18and 13 drugs for 3CL pro and PL pro , respectively, whose solutions 171 specifically fit into the active site and interacts with the above said residues along with others. Table 1 . and PL pro dual-inhibitor, are also symptoms reliever or risk reducer for cardiovascular, a for each compound was recorded, as shown in Table 2 . 292 Table 2 . ADMET properties of screened compounds. His272, and Asp286 were only considered as positive (Fig. 3) . Furthermore, the assessment 343 of such positive drugs was done to find the type of interactions and list of common drugs 344 being positive for both proteases. 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