Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs

Abstract

The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs in silico. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.

Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs

“…We are aware of two other studies where docking experiments were used to predict binding of existing pharmaceuticals to the SARS-CoV-2 PL pro (Devaraj et al, 2007;World Health Organization, 2020). Both prior studies relied on homology modeling of part (Arya et al, 2020) or the entire SARS-CoV PL pro . Wu et al (2020) studied 2,924 compounds from ZINC Drug Database, as well as 78 known antivirals; while Arya et al (2020) studied 2,525 FDA-approved compounds from DrugBank and the ZINC 15 database.…”

“…In view of the urgent need for effective treatments and the high cost of developing new drugs (both in terms of time and resources), repurposing FDA-approved drugs is an efficient strategy for identifying drug candidates that can be used immediately in the COVID-19 pandemic (Tan et al, 2004;Kouznetsova, Huang & Tsigelny, 2020). In a previous report, we (Kouznetsova, Huang & Tsigelny, 2020) and others (Kandeel & Al-Nazawi, 2020;Arya et al, 2020;Plewczynski et al, 2007;Ton et al, 2020) have used molecular modeling studies to identify FDA-approved drugs and other compounds (Arya et al, 2020;Ton et al, 2020;Alamri, Tahir ul Qamar & Alqahtani, 2020) that are predicted to bind to 3CL pro . The list of potential inhibitors includes bleomycin, mithramycin, and goserelin, as well as others that may be effective (Kouznetsova, Huang & Tsigelny, 2020).…”

<em></em><strong><em>In silico</em> Repositioning for Dual Inhibitor Discovery of SARS-CoV-2 (COVID-19) 3C-like Protease and Papain-like Peptidase</strong>

“…The MM-GBSA calculation was performed based on the best pose structure obtained from XP docking complexes. (26). The co-crystallized ligand in 3E9S PDB entry also matched and superimposed with the created model.…”

“…The active site is located at the interface of the thumb and palm sub-domains and contains a classic catalytic triad, composed of Cys856-His1017-Asp1031, adjacent to the flexible BL2 loop containing Trp851 (according to the homology modeled structure residue numbering). The enzyme has four substrate recognition subsites (S1-S4) (26). Figure 4b represents the active site, the residues and the related subsites.…”

“…1-21), PLpro (No [15][16][17][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and the corresponding dual inhibitor (No [15][16][17][19][20][21], mechanism of action and therapeutic indication.…”