Potential SARS-CoV-2 main protease inhibitors

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (M^pro). The main proteases of different coronaviruses, including SARS-CoV-2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), share a structurally conserved substrate-binding region that can be exploited to design new protease inhibitors. With the recent reporting of the X-ray crystal structure of the SARS-CoV-2 M^pro, studies to discover M^pro inhibitors using both virtual and in vitro screening are progressing rapidly. This review focusses on the recent developments in the search for small-molecule inhibitors targeting the SARS-CoV-2 M^pro.

Graphical abstract

Figure 1

Mechanism of action of cysteine proteases.

Figure 2

(a) The ribbon representation of the crystal structure of the SARS-CoV-2 M^pro from PDB ID: 6Y2F. Domains I, II and III are displayed in red, yellow and blue, respectively. The connection region between II and III is in white and the catalytic dyad residues (His41 and Cys145) are in solid spheres. (b) Protease active site residues that are involved in the inhibitor interactions. (c) Multiple sequence alignment of SARS-CoV-2 (Gene Bank ID: 045512.2), SARS-CoV (Gene Bank ID: NC004718.3) and MERS-CoV (Gene Bank ID: KT006149.2) using CLUSTAL W (1.83) . Twelve residues that differ between SARS-CoV-2 and SARS-CoV are marked in red. The catalytic residues are marked in green. Active site residues are marked out with arrows. (d) Structure alignment between SARS-CoV in white (PDB ID: 2H2Z) and SARS-CoV-2 in red (PDB ID: 6LU7). Residues that differ between the two sequences are shown as solid spheres. The catalytic dyad residues, Cys145 and His41, are shown in yellow. (e) The dimer structure from PDB ID: 6Y2G. Domains I, II, and III of monomer A are in red, yellow and blue, respectively, whereas monomer B is in white. The catalytic dyad of each dimer is also shown. The dimer-interacting surface is situated on the opposite side of the active site.

Figure 3

(a) Covalently bound inhibitors used for the SARS-CoV-2 M^pro (N3) and the SARS-CoV M^pro (N1) . (b) Potential inhibitors binding covalently to Cys145 of the SARS-CoV-2 M^pro. (c) α-Ketoamides display SARS-CoV-2 M^pro inhibitory activity. Compared with Michael acceptors, the thiohemiacetal intermediate formed is stabilized by an additional hydrogen bond with the catalytic center of the protease. Highlighted here are compounds 11 r and 13b, with their peptide regions designated P1, P1′, P2 and P3 .

Figure 4

(a) Compounds 11a and 11b display excellent antiviral activity . (b) Nelfinavir, kaempferol, aliskiren, rhein, withaferin-A, quercetin, naringenin, dipyridamole and rosuvastatin, promising inhibitors of the SARS-CoV-2 M^pro, , .

Figure 5

Molecular docking of compound 621, ZINC000541677852 and mitoxantrone showed their high binding affinity for the SARS-CoV-2 M^pro, , .

Figure 6

(a) Molecules designed by pharmacophore-based virtual screening, LIGANN, comparative docking and AI-based lead optimization for the SARS-CoV-2 M^pro, , , . (b) Computational drug repurposing, phytochemical screening and investigation of FDA-approved drugs against the SARS-CoV-2 M^pro yielded sincalide, pentagastrin, elbasvir, carfilzomib, eravacycline, valrubicin, lopinavir, myricitrin, methyl rosmarinate and 5,7,3′,4′-tetrahydroxy-2'-(3,3-dimethylallyl) isoflavone as potential inhibitors , , . (c)In silico screening of several natural products revealed phycocyanobilin, eucalyptol, jensenone, nigellidine, hesperidin and rutin to have potential SARS-CoV-2 M^pro inhibitory activity, along with mepacrine, a derivative of chloroquine , , , , , .

Figure 7

(a) Studies conducted on Ayurvedic natural products, plant-based natural products and marine-based natural products gave the best results for myricitrin, δ-viniferin, taiwanhomoflavone-A, lactucopicrin 15-oxalate, nympholide-A, biorobin, phyllaemblicin-B, oleanic acid and heptafuhalol-A , , . (b) Screening of repurposed drugs against the SARS-CoV-2 M^pro yielded the highest binding affinities for rifampicin, ciclesonide, ribavirin (in combination with vitamin B12, nicotinamide and telbivudine) and oseltamivir (in combination with lopinavir and ritonavir). Telcagepant, vidupiprant, poziotinib and fostamatinib were ranked the best, based on the SCAR protocol for screening covalent ligands against the SARS-CoV-2 M^pro, , , .

Figure 8

Molecules most recently reported to demonstrate potential in silico SARS-CoV-2 M^pro inhibitory activity , , , , , , , , , , , , , , , , , .